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Moriarty N, Fraser TD, Hunt CPJ, Eleftheriou G, Kauhausen JA, Thompson LH, Parish CL. Exercise promotes the functional integration of human stem cell-derived neural grafts in a rodent model of Parkinson's disease. Stem Cell Reports 2025; 20:102480. [PMID: 40280136 DOI: 10.1016/j.stemcr.2025.102480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
Human pluripotent stem cell (hPSC)-derived dopamine neurons can functionally integrate and reverse motor symptoms in Parkinson's disease models, motivating current clinical trials. However, dopamine neuron proportions remain low and their plasticity inferior to fetal tissue grafts. Evidence shows exercise can enhance neuron survival and plasticity, warranting investigation for hPSC-derived neural grafts. We show voluntary exercise (wheel running) significantly increases graft plasticity, accelerating motor recovery in animals receiving ectopic, but not homotopic, placed grafts, suggestive of threshold requirements. Plasticity was accompanied by increased phosphorylated extracellular signal-regulated kinase (ERK+) cells in the graft (and host), reflective of mitogen-activated protein kinase (MAPK)-ERK signaling, a downstream target of glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), proteins that were also elevated. Verifying improved graft integration was the increase in cFos+ postsynaptic striatal neurons. These findings have direct implications for the adoption of physical therapy-based approaches to enhance neural transplantation outcomes in future Parkinson's disease clinical trials.
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Affiliation(s)
- Niamh Moriarty
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Tyra D Fraser
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Cameron P J Hunt
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Georgia Eleftheriou
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Jessica A Kauhausen
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Lachlan H Thompson
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Charles Perkins Institute, The University of Sydney, Sydney, NSW, Australia.
| | - Clare L Parish
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
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2
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Mercado NM, Szarowicz C, Stancati JA, Sortwell CE, Boezwinkle SA, Collier TJ, Caulfield ME, Steece-Collier K. Advancing age and the rs6265 BDNF SNP are permissive to graft-induced dyskinesias in parkinsonian rats. NPJ Parkinsons Dis 2024; 10:163. [PMID: 39179609 PMCID: PMC11344059 DOI: 10.1038/s41531-024-00771-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
The rs6265 single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor is a common variant that alters therapeutic outcomes for individuals with Parkinson's disease (PD). We previously investigated the effects of this SNP on the experimental therapeutic approach of neural grafting, demonstrating that young adult parkinsonian rats carrying the variant Met allele exhibited enhanced graft function compared to wild-type rats and also exclusively developed aberrant graft-induced dyskinesias (GID). Aging is the primary risk factor for PD and reduces graft efficacy. Here we investigated whether aging interacts with this SNP to further alter cell transplantation outcomes. We hypothesized that aging would reduce enhancement of graft function associated with this genetic variant and exacerbate GID in all grafted subjects. Unexpectedly, beneficial graft function was maintained in aged rs6265 subjects. However, aging was permissive to GID induction, regardless of genotype, with the greatest incidence and severity found in rs6265-expressing animals.
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Affiliation(s)
- Natosha M Mercado
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
| | - Carlye Szarowicz
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Jennifer A Stancati
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
| | - Caryl E Sortwell
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
- Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI, 49503, USA
| | - Samuel A Boezwinkle
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Timothy J Collier
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
- Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI, 49503, USA
| | - Margaret E Caulfield
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
| | - Kathy Steece-Collier
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.
- Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI, 49503, USA.
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Bruno A, Milillo C, Anaclerio F, Buccolini C, Dell’Elice A, Angilletta I, Gatta M, Ballerini P, Antonucci I. Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases. Int J Mol Sci 2024; 25:976. [PMID: 38256050 PMCID: PMC10815412 DOI: 10.3390/ijms25020976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.
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Affiliation(s)
- Annalisa Bruno
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Cristina Milillo
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Federico Anaclerio
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Carlotta Buccolini
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Anastasia Dell’Elice
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Ilaria Angilletta
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Marco Gatta
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Patrizia Ballerini
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Ivana Antonucci
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.B.); (C.M.); (C.B.); (A.D.); (I.A.)
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
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Lindvall O. History of cellular grafting for central nervous system repair-A clinical perspective. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:15-40. [PMID: 39341652 DOI: 10.1016/b978-0-323-90120-8.00011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
As late as in the 1970s, the evidence supporting that brain function might be restored by replacing dead cells by transplantation of new healthy cells was scarce in experimental animals and lacking in humans. Repairing the human brain was regarded as completely unrealistic by clinicians. Fifty years later, the situation is very different, and cellular grafting has reached patient application in several conditions affecting the CNS. The clinical studies performed so far have shown that cellular grafts can survive, grow, and function also in the diseased adult human brain. However, no proven treatment based on cell transplantation is currently available for any brain disorder. Here, the history of cellular grafting is described from a clinical perspective, including some of the preclinical work that has formed the basis for its translation to patient application. The focus is on cell transplantation for Parkinson disease, which in many ways is paving the way for this field of research. The chapter gives an account of the scientific milestones, the ups and downs, as well as the positive and negative reactions from the scientific and clinical community, and how this research field despite many obstacles has continued to move forward over more than four decades.
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Affiliation(s)
- Olle Lindvall
- Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden; Division of Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
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Harary PM, Jgamadze D, Kim J, Wolf JA, Song H, Ming GL, Cullen DK, Chen HI. Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson's Disease and Cortical Injury. Brain Sci 2023; 13:1654. [PMID: 38137103 PMCID: PMC10741697 DOI: 10.3390/brainsci13121654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/16/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through "bystander effects" and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson's disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson's disease as well as the use of structured grafts such as brain organoids for cortical repair.
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Affiliation(s)
- Paul M. Harary
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
| | - Dennis Jgamadze
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
| | - Jaeha Kim
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
| | - John A. Wolf
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Guo-li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - D. Kacy Cullen
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - H. Isaac Chen
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.M.H.)
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Kirkeby A, Nelander J, Hoban DB, Rogelius N, Bjartmarz H, Storm P, Fiorenzano A, Adler AF, Vale S, Mudannayake J, Zhang Y, Cardoso T, Mattsson B, Landau AM, Glud AN, Sørensen JC, Lillethorup TP, Lowdell M, Carvalho C, Bain O, van Vliet T, Lindvall O, Björklund A, Harry B, Cutting E, Widner H, Paul G, Barker RA, Parmar M. Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson's disease, STEM-PD. Cell Stem Cell 2023; 30:1299-1314.e9. [PMID: 37802036 DOI: 10.1016/j.stem.2023.08.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 07/06/2023] [Accepted: 08/31/2023] [Indexed: 10/08/2023]
Abstract
Cell replacement therapies for Parkinson's disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022.
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Affiliation(s)
- Agnete Kirkeby
- Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Jenny Nelander
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Deirdre B Hoban
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Nina Rogelius
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Hjálmar Bjartmarz
- Department of Neurosurgery, Skåne University Hospital, 221 85 Lund, Sweden
| | - Petter Storm
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Alessandro Fiorenzano
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Andrew F Adler
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Shelby Vale
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Janitha Mudannayake
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Yu Zhang
- Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Tiago Cardoso
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Bengt Mattsson
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Anne M Landau
- Department of Nuclear Medicine & PET-Center and Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
| | - Andreas N Glud
- Center for Experimental Neuroscience (CENSE), Department of Neurosurgery, Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Jens C Sørensen
- Center for Experimental Neuroscience (CENSE), Department of Neurosurgery, Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Thea P Lillethorup
- Department of Nuclear Medicine & PET-Center and Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
| | - Mark Lowdell
- Centre for Cell, Gene and Tissue Therapeutics, Royal Free NHS Foundation Trust, Royal Free Hospital, London NW3 2QG, UK
| | - Carla Carvalho
- Centre for Cell, Gene and Tissue Therapeutics, Royal Free NHS Foundation Trust, Royal Free Hospital, London NW3 2QG, UK
| | - Owen Bain
- Centre for Cell, Gene and Tissue Therapeutics, Royal Free NHS Foundation Trust, Royal Free Hospital, London NW3 2QG, UK
| | | | - Olle Lindvall
- Lund Stem Cell Center and Department of Clinical Sciences Lund, Lund University, 221 84 Lund, Sweden
| | - Anders Björklund
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden
| | - Bronwen Harry
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK
| | - Emma Cutting
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK
| | - Håkan Widner
- Department of Neurology, Skåne University Hospital, 221 85 Lund, Sweden
| | - Gesine Paul
- Department of Neurology, Skåne University Hospital, 221 85 Lund, Sweden; Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden
| | - Roger A Barker
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK; Wellcome-MRC Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK
| | - Malin Parmar
- Wallenberg Neuroscience Center, MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
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Wang F, Sun Z, Peng D, Gianchandani S, Le W, Boltze J, Li S. Cell-therapy for Parkinson's disease: a systematic review and meta-analysis. J Transl Med 2023; 21:601. [PMID: 37679754 PMCID: PMC10483810 DOI: 10.1186/s12967-023-04484-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Cell-based strategies focusing on replacement or protection of dopaminergic neurons have been considered as a potential approach to treat Parkinson's disease (PD) for decades. However, despite promising preclinical results, clinical trials on cell-therapy for PD reported mixed outcomes and a thorough synthesis of these findings is lacking. We performed a systematic review and meta-analysis to evaluate cell-therapy for PD patients. METHODS We systematically identified all clinical trials investigating cell- or tissue-based therapies for PD published before July 2023. Out of those, studies reporting transplantation of homogenous cells (containing one cell type) were included in meta-analysis. The mean difference or standardized mean difference in quantitative neurological scale scores before and after cell-therapy was analyzed to evaluate treatment effects. RESULTS The systematic literature search revealed 106 articles. Eleven studies reporting data from 11 independent trials (210 patients) were eligible for meta-analysis. Disease severity and motor function evaluation indicated beneficial effects of homogenous cell-therapy in the 'off' state at 3-, 6-, 12-, or 24-month follow-ups, and for motor function even after 36 months. Most of the patients were levodopa responders (61.6-100% in different follow-ups). Cell-therapy was also effective in improving the daily living activities in the 'off' state of PD patients. Cells from diverse sources were used and multiple transplantation modes were applied. Autografts did not improve functional outcomes, while allografts exhibited beneficial effects. Encouragingly, both transplantation into basal ganglia and to areas outside the basal ganglia were effective to reduce disease severity. Some trials reported adverse events potentially related to the surgical procedure. One confirmed and four possible cases of graft-induced dyskinesia were reported in two trials included in this meta-analysis. CONCLUSIONS This meta-analysis provides preliminary evidence for the beneficial effects of homogenous cell-therapy for PD, potentially to the levodopa responders. Allogeneic cells were superior to autologous cells, and the effective transplantation sites are not limited to the basal ganglia. PROSPERO registration number: CRD42022369760.
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Affiliation(s)
- Fang Wang
- Department of Neurology, Central Hospital of Dalian University of Technology, Dalian, China
| | - Zhengwu Sun
- Department of Clinical Pharmacy, Central Hospital of Dalian University of Technology, Dalian, China
| | - Daoyong Peng
- Department of Neurology, Central Hospital of Dalian University of Technology, Dalian, China
| | - Shikha Gianchandani
- School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
| | - Weidong Le
- Institute of Neurology, Sichuan Academy of Medical Sciences, Sichuan Provincial Hospital, Chengdu, China
| | - Johannes Boltze
- School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
| | - Shen Li
- Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi Road, Beijing, 100038, China.
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.
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Barker RA, Björklund A. Restorative cell and gene therapies for Parkinson's disease. HANDBOOK OF CLINICAL NEUROLOGY 2023; 193:211-226. [PMID: 36803812 DOI: 10.1016/b978-0-323-85555-6.00012-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor features of this condition as well as some of the cognitive problems. The importance of this pathological event is evident through the clinical benefits that are seen when patients with PD are treated with dopaminergic agents, at least in early-stage disease. However, these agents create problems of their own through stimulation of more intact dopaminergic networks within the central nervous system causing major neuropsychiatric problems including dopamine dysregulation. In addition, over time the nonphysiological stimulation of striatal dopamine receptors by l-dopa containing drugs leads to the genesis of l-dopa-induced dyskinesias that can become very disabling in many cases. As such, there has been much interest in trying to better reconstitute the dopaminergic nigrostriatal pathway using either factors to regrow it, cells to replace it, or gene therapies to restore dopamine transmission in the striatum. In this chapter, we lay out the rationale, history and current status of these different therapies as well as highlighting where the field is heading and what new interventions might come to clinic in the coming years.
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Affiliation(s)
- Roger A Barker
- Department of Clinical Neuroscience, Cambridge Centre for Brain Repair, Cambridge, United Kingdom.
| | - Anders Björklund
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
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Kim J, Inbo H, Kim HS, Kim W, Jang SJ, Min K, Kim SH, Bae SH, Jeong YH, Kim B, Kim C, Schwarz SC, Schwarz J, Cho KG, Chung SS, Moon J. First Clinical Report on the Treatment of Parkinson's Disease with Fetal Midbrain Precursor Cells. Mov Disord 2023; 38:589-603. [PMID: 36692025 DOI: 10.1002/mds.29316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Because human fetal ventral mesencephalic tissue grafts provide promising results in ameliorating Parkinson's disease-implicated motor dysfunctions, human fetal midbrain-derived dopamine neuronal precursor cells are considered good candidates for cell-based therapy for Parkinson's disease in that large quantities of cells can be supplied through a good manufacturing practice-compliant system. OBJECTIVE We conducted a prospective, phase I/IIa, dose-escalation, open-label "first-in-human" clinical trial with fetal neural precursor cells to assess their safety and therapeutic efficacy in patients with idiopathic Parkinson's disease. METHODS Fifteen patients were assigned to receive three different doses of cells (4 × 106 , 12 × 106 , and 40 × 106 cells) and completed a 12-month follow-up. The primary outcome was safety, by measuring the presence of grade 3 or higher cells according to National Cancer Institute guidelines and any contaminated cells. Secondary outcomes assessed motor and neurocognitive function, as well as the level of dopamine transporters, by positron emission tomography-computed tomography. RESULTS Although a pronation-supination and hand/arm movement performance was remarkably enhanced in all three groups (all P < 0.05), the medium- and high-dose-treated groups exhibited significant improvement in Unified Parkinson's Disease Rating Scale Part III only up to 26.16% and 40%, respectively, at 12 months after transplantation without any serious clinical complications or graft-induced dyskinesia in all patients. However, the motor improvements did not correlate with increase in the dopamine transporter on positron emission tomography images. CONCLUSIONS Our results primarily demonstrate the safety and plausible dose-dependent efficacy of human fetal midbrain-derived dopamine neuronal precursor cells for idiopathic Parkinson's disease. © 2023 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Joopyoung Kim
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Han Inbo
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Hyun Sook Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - WonChan Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Su Jin Jang
- Department of Nuclear Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Kyunghoon Min
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Sang Heum Kim
- Department of Neuroradiology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Sang-Hun Bae
- Department of Biotechnology, CHA University, Seongnam, Republic of Korea
| | - Yun-Hwa Jeong
- Department of Biotechnology, CHA University, Seongnam, Republic of Korea
| | - Borah Kim
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Chul Kim
- Department of Biotechnology, CHA University, Seongnam, Republic of Korea
| | - Sigrid C Schwarz
- Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.,German Center for Neurodegenerative Diseases, Technical University Munich, Munich, Germany
| | - Johannes Schwarz
- Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.,Geriatric Hospital Haag, Haag, Germany
| | - Kyung Gi Cho
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Sang-Sup Chung
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Jisook Moon
- Department of Biotechnology, CHA University, Seongnam, Republic of Korea
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10
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Lloyd K, Lawton M, Whone A. Practically Defined Off-State Dyskinesia Following Repeated Intraputamenal Glial Cell Line-Derived Neurotrophic Factor Administration. Mov Disord 2023; 38:104-112. [PMID: 36444971 DOI: 10.1002/mds.29262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 09/09/2022] [Accepted: 10/07/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND We recently showed that by employing an enhanced drug-delivery approach, repeated administration of glial cell line-derived neurotrophic factor (GDNF) can produce a spatially distributed increased 18 F-DOPA positron emission tomography (PET) uptake, suggesting sprouting of dopaminergic terminals throughout the putamen structure. Despite this, we failed to prove a significant measurable clinical response. Since, however, we have identified a subject demonstrating a temporal relationship between repeated GDNF infusions and dyskinesia arising in the practically defined off (pracoff) state. OBJECTIVES To describe the development of pracoff dyskinesia across our study population and consider its utility as an indicator that trophic factor-induced terminal sprouting can affect enhanced endogenous dopamine levels. METHODS This was a blinded retrospective analysis of videotaped motor assessments at eight weekly study visits. Dyskinesia in the pracoff and supramaximal on state were rated using the Clinical Dyskinesia Rating Scale. Logistic regression was employed to explore the predictors of pracoff dyskinesia. Generalized estimated equations were used to estimate the cumulative effect of repeated GDNF infusions. RESULTS Mild-moderate choreiform dyskinesia in the pracoff state were seen in 47 assessments in 17 (n = 41) subjects. During the 18-month timeframe, each subsequent 8-week period of receiving GDNF increased the risk of demonstrating pracoff state dyskinesia by 34% (odds ratio [OR], 1.34 (95% confidence interval [CI], 1.20, 1.50); P < 0.001). An increasing supramaximal on dyskinesia score (OR, 1.17 [95% CI, 1.07, 1.30]; P = 0.001) also increased the likelihood of pracoff dyskinesia at that visit. CONCLUSIONS We report the first description of increasingly prevalent pracoff-state dyskinesia developing during the course of a trophic factor study. This may provide a surrogate marker that GDNF can enable recovery of endogenous dopamine release even in advanced Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Katherine Lloyd
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.,Department of Neurology, North Bristol National Health Service (NHS) Trust, Bristol, United Kingdom
| | - Michael Lawton
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Alan Whone
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.,Department of Neurology, North Bristol National Health Service (NHS) Trust, Bristol, United Kingdom
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11
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Characterization of Human-Induced Neural Stem Cells and Derivatives following Transplantation into the Central Nervous System of a Nonhuman Primate and Rats. Stem Cells Int 2022; 2022:1396735. [PMID: 36618021 PMCID: PMC9812602 DOI: 10.1155/2022/1396735] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 05/18/2022] [Accepted: 05/20/2022] [Indexed: 12/29/2022] Open
Abstract
Neural stem cells (NSCs) and derivatives are potential cellular sources to treat neurological diseases. In the current study, we reprogrammed human peripheral blood mononuclear cells into induced NSCs (iNSCs) and inserted GFP gene into the AAVS1 site for graft tracing. Targeted integration of GFP does not affect the proliferation and differentiation capacity of iNSCs. iNSC-GFP can be further differentiated into dopaminergic precursors (DAPs) and motor neuron precursors (MNPs), respectively. iNSCs were engrafted into the motor cortex and iNSC-DAPs into the striatum and substantia nigra (SN) of a nonhuman primate, respectively. The surviving iNSCs could respond to the microenvironment of the cortex and spontaneously differentiate into mature neurons that extended neurites. iNSC-DAPs survived well and matured into DA neurons following transplantation into the striatum and SN. iNSC-MNPs could also survive and turn into motor neurons after being engrafted into the spinal cord of rats. The results suggest that iNSCs and derivatives have a potential to be used for the treatment of neurological diseases.
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12
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Li J, Li N, Wei J, Feng C, Chen Y, Chen T, Ai Z, Zhu X, Ji W, Li T. Genetically engineered mesenchymal stem cells with dopamine synthesis for Parkinson's disease in animal models. NPJ Parkinsons Dis 2022; 8:175. [PMID: 36550118 PMCID: PMC9780305 DOI: 10.1038/s41531-022-00440-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Although striatal delivery of three critical genes for dopamine synthesis by viruses is a potential clinical approach for treating Parkinson's disease (PD), the approach makes it difficult to finely control dopamine secretion amounts and brings safety concerns. Here, we generate genetically engineered mesenchymal stem cells encoding three critical genes for dopamine synthesis (DOPA-MSCs). DOPA-MSCs retain their MSC identity and stable ability to secrete dopamine during passaging. Following transplantation, DOPA-MSCs reinstate striatal dopamine levels and correct motor function in PD rats. Importantly, after grafting into the caudate and putamen, DOPA-MSCs provide homotopic reconstruction of midbrain dopamine pathways by restoring striatal dopamine levels, and safely and long-term (up to 51 months) correct motor disorders and nonmotor deficits in acute and chronic PD rhesus monkey models of PD even with advanced PD symptoms. The long-term benefits and safety results support the idea that the development of dopamine-synthesized engineered cell transplantation is an important strategy for treating PD.
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Affiliation(s)
- Jun Li
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Nan Li
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Jingkuan Wei
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Chun Feng
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Yanying Chen
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Tingwei Chen
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Zongyong Ai
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Xiaoqing Zhu
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Weizhi Ji
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
| | - Tianqing Li
- grid.218292.20000 0000 8571 108XState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, 650500 Kunming, Yunnan China ,grid.218292.20000 0000 8571 108XYunnan Key Laboratory of Primate Biomedical Research, 650500 Kunming, Yunnan China
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13
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Salahi S, Mousavi MA, Azizi G, Hossein-Khannazer N, Vosough M. Stem Cell-based and Advanced Therapeutic Modalities for Parkinson's Disease: A Risk-effectiveness Patient-centered Analysis. Curr Neuropharmacol 2022; 20:2320-2345. [PMID: 35105291 PMCID: PMC9890289 DOI: 10.2174/1570159x20666220201100238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/14/2022] [Accepted: 01/26/2022] [Indexed: 12/29/2022] Open
Abstract
Treatment of Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is currently considered a challenging issue since it causes substantial disability, poor quality of life, and mortality. Despite remarkable progress in advanced conventional therapeutic interventions, the global burden of the disease has nearly doubled, prompting us to assess the riskeffectiveness of different treatment modalities. Each protocol could be considered as the best alternative treatment depending on the patient's situation. Prescription of levodopa, the most effective available medicine for this disorder, has been associated with many complications, i.e., multiple episodes of "off-time" and treatment resistance. Other medications, which are typically used in combination with levodopa, may have several adverse effects as well. As a result, the therapies that are more in line with human physiology and make the least interference with other pathways are worth investigating. On the other hand, remaining and persistent symptoms after therapy and the lack of effective response to the conventional approaches have raised expectations towards innovative alternative approaches, such as stem cell-based therapy. It is critical to not overlook the unexplored side effects of innovative approaches due to the limited number of research. In this review, we aimed to compare the efficacy and risk of advanced therapies with innovative cell-based and stemcell- based modalities in PD patients. This paper recapitulated the underlying factors/conditions, which could lead us to more practical and established therapeutic outcomes with more advantages and few complications. It could be an initial step to reconsider the therapeutic blueprint for patients with Parkinson's disease.
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Affiliation(s)
- Sarvenaz Salahi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Alsadat Mousavi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research, Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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14
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Lane EL, Lelos MJ. Defining the unknowns for cell therapies in Parkinson's disease. Dis Model Mech 2022; 15:dmm049543. [PMID: 36165848 PMCID: PMC9555765 DOI: 10.1242/dmm.049543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD.
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Affiliation(s)
- Emma L. Lane
- Cardiff School of Pharmacy and Pharmaceutical Sciences, King Edward VII Avenue, Cardiff University, Cardiff CF10 3NB, UK
| | - Mariah J. Lelos
- School of Biosciences, Museum Avenue, Cardiff University, Cardiff CF10 3AX, UK
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15
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Wianny F, Dzahini K, Fifel K, Wilson CRE, Bernat A, Dolmazon V, Misery P, Lamy C, Giroud P, Cooper HM, Knoblauch K, Procyk E, Kennedy H, Savatier P, Dehay C, Vezoli J. Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103827. [PMID: 35137562 PMCID: PMC8981458 DOI: 10.1002/advs.202103827] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/14/2022] [Indexed: 05/10/2023]
Abstract
Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.
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Affiliation(s)
- Florence Wianny
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- PrimastemBron69500France
| | - Kwamivi Dzahini
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- PrimastemBron69500France
| | - Karim Fifel
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- Present address: International Institute for Integrative Sleep Medicine (WPI‐IIIS)University of TsukubaTsukubaIbaraki305‐8575Japan
| | - Charles Robert Eden Wilson
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Agnieszka Bernat
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- Present address: Laboratory of Molecular DiagnosticsDepartment of BiotechnologyInter‐collegiate Faculty of BiotechnologyUniversity of Gdańsk and Medical University of GdańskGdańsk80‐307Poland
- Present address: Laboratory of Experimental EmbryologyInstitute of Genetics and Animal BiotechnologyPolish Academy of SciencesWarsaw05‐552Poland
| | - Virginie Dolmazon
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Pierre Misery
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Camille Lamy
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Pascale Giroud
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Howard Michael Cooper
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Kenneth Knoblauch
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- National Centre for OpticsVision and Eye CareFaculty of Health and Social SciencesUniversity College of Southeast NorwayKongsbergN‐3603Norway
| | - Emmanuel Procyk
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
| | - Henry Kennedy
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- Institute of NeuroscienceState Key Laboratory of NeuroscienceChinese Academy of Sciences (CAS) Key Laboratory of Primate NeurobiologyShanghai200031China
| | - Pierre Savatier
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- PrimastemBron69500France
| | - Colette Dehay
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- PrimastemBron69500France
| | - Julien Vezoli
- Univ Lyon, Université Claude Bernard Lyon 1Inserm U1208Stem Cell and Brain Research InstituteBron69500France
- Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck SocietyFrankfurt60528Germany
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16
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Lane EL, Harrison DJ, Ramos‐Varas E, Hills R, Turner S, Lelos MJ. Spontaneous Graft-Induced Dyskinesias Are Independent of 5-HT Neurons and Levodopa Priming in a Model of Parkinson's Disease. Mov Disord 2022; 37:613-619. [PMID: 34766658 PMCID: PMC9208367 DOI: 10.1002/mds.28856] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/28/2021] [Accepted: 10/20/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The risk of graft-induced dyskinesias (GIDs) presents a major challenge in progressing cell transplantation as a therapy for Parkinson's disease. Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa-induced dyskinesia. OBJECTIVE To elucidate the mechanisms of GIDs. METHODS Neonatally desensitized, dopamine denervated rats received intrastriatal grafts of human embryonic stem cells (hESCs) differentiated into either ventral midbrain dopaminergic progenitor (vmDA) (n = 15) or ventral forebrain cells (n = 14). RESULTS Of the eight rats with surviving grafts, two vmDA rats developed chronic spontaneous GIDs, which were observed at 30 weeks post-transplantation. GIDs were inhibited by D2 -like receptor antagonists and not affected by 5-HT1A/1B/5-HT6 agonists/antagonists. Grafts in GID rats showed more microglial activation and lacked serotonin neurons. CONCLUSIONS These findings argue against current thinking that rats do not develop spontaneous GID and that serotonin neurons are causative, rather indicating that GID can be induced in rats by hESC-derived dopamine grafts and, critically, can occur independently of both previous levodopa exposure and grafted serotonin neurons. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Emma L. Lane
- School of Pharmacy and Pharmaceutical SciencesCardiff UniversityCardiffUnited Kingdom
| | - David J. Harrison
- Brain Repair Group, School of BiosciencesCardiff UniversityCardiffUnited Kingdom
| | - Elena Ramos‐Varas
- Brain Repair Group, School of BiosciencesCardiff UniversityCardiffUnited Kingdom
| | - Rachel Hills
- Brain Repair Group, School of BiosciencesCardiff UniversityCardiffUnited Kingdom
| | - Sophie Turner
- Brain Repair Group, School of BiosciencesCardiff UniversityCardiffUnited Kingdom
| | - Mariah J. Lelos
- School of Pharmacy and Pharmaceutical SciencesCardiff UniversityCardiffUnited Kingdom
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17
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A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells. Cell Stem Cell 2022; 29:434-448.e5. [PMID: 35180398 DOI: 10.1016/j.stem.2022.01.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/24/2021] [Accepted: 01/25/2022] [Indexed: 12/12/2022]
Abstract
Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine levels and correction of motor function and also connectivity with additional mDA target nuclei not well innervated by ectopic grafts. These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.
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18
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Drew CJG, Busse M. Considerations for clinical trial design and conduct in the evaluation of novel advanced therapeutics in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 166:235-279. [PMID: 36424094 DOI: 10.1016/bs.irn.2022.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The recent advances in the development of potentially disease modifying cell and gene therapies for neurodegenerative disease has resulted in the production of a number of promising novel therapies which are now moving forward to clinical evaluation. The robust evaluation of these therapies pose a significant number of challenges when compared to more traditional evaluations of pharmacotherapy, which is the current mainstay of neurodegenerative disease symptom management. Indeed, there is an inherent complexity in the design and conduct of these trials at multiple levels. Here we discuss specific aspects requiring consideration in the context of investigating novel cell and gene therapies for neurodegenerative disease. This extends to overarching trial designs that could be employed and the factors that underpin design choices such outcome assessments, participant selection and methods for delivery of cell and gene therapies. We explore methods of data collection that may improve efficiency in trials of cell and gene therapy to maximize data sharing and collaboration. Lastly, we explore some of the additional context beyond efficacy evaluations that should be considered to ensure implementation across relevant healthcare settings.
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Affiliation(s)
- Cheney J G Drew
- Centre For Trials Research, Cardiff University, Cardiff, United Kingdom; Brain Repair and Intracranial Neurotherapeutics Unit (BRAIN), College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
| | - Monica Busse
- Centre For Trials Research, Cardiff University, Cardiff, United Kingdom; Brain Repair and Intracranial Neurotherapeutics Unit (BRAIN), College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
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19
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Morizane A, Takahashi J. Evading the Immune System: Immune Modulation and Immune Matching in Cell Replacement Therapies for Parkinson's Disease. JOURNAL OF PARKINSONS DISEASE 2021; 11:S167-S172. [PMID: 34024783 PMCID: PMC8543266 DOI: 10.3233/jpd-212608] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Stem cell-based therapies for Parkinson’s disease are now being applied clinically. Notably, studies have shown that controlling the graft-induced immune response improves the results. In this mini-review, we concisely summarize current approaches used for this control. We focus on four modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation with human leukocyte antigen-matching and allogeneic transplantation without, and finally the application of “universal” pluripotent stem cells. We also discuss immuno-suppressive treatments and the monitoring of immune reactions in the brain.
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Affiliation(s)
- Asuka Morizane
- Department of Regenerative Medicine, Center for Clinical Research and Innovation, Kobe City Medical Center General Hospital, Hyogo, Japan.,Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Jun Takahashi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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20
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Li JY, Li W. Postmortem Studies of Fetal Grafts in Parkinson's Disease: What Lessons Have We Learned? Front Cell Dev Biol 2021; 9:666675. [PMID: 34055800 PMCID: PMC8155361 DOI: 10.3389/fcell.2021.666675] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/06/2021] [Indexed: 12/28/2022] Open
Abstract
Neural transplantation is a potential therapeutic method for Parkinson’s disease (PD). Fetal dopaminergic (DA) neurons have been important transplantation cell sources in the history of replacement therapy for PD. Several decades of preclinical animal experiments and clinical trials using fetal DA neuron transplantation in PD therapy have shown not only promising results but also problems. In order to reveal possible factors influencing the clinical outcomes, we reviewed fetal DA neuron transplantation therapies from 1970s to present, with a special focus on postmortem studies. Firstly, we gave a general description of the clinical outcomes and neuroanatomy of grafted cases; secondly, we summarized the main available postmortem studies, including the cell survival, reinnervation, and pathology development. In the end, we further discussed the link between function and structure of the grafts, seeking for the possible factors contributing to a functional graft. With our review, we hope to provide references for future transplantation trials from a histological point of view.
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Affiliation(s)
- Jia-Yi Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Wen Li
- Laboratory of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical University, Shenyang, China.,Neural Plasticity and Repair Unit, Wallenberg Neuroscience Centre, Department of Experimental Medical Science, Lund University, Lund, Sweden
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21
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Shrigley S, Nilsson F, Mattsson B, Fiorenzano A, Mudannayake J, Bruzelius A, Ottosson DR, Björklund A, Hoban DB, Parmar M. Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson's Disease. JOURNAL OF PARKINSONS DISEASE 2021; 11:515-528. [PMID: 33361611 PMCID: PMC8150478 DOI: 10.3233/jpd-202366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson's disease (PD) and they provide the option of using the patient's own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. OBJECTIVE To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. METHODS Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. RESULTS Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. CONCLUSION This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.
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Affiliation(s)
- Shelby Shrigley
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Fredrik Nilsson
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Bengt Mattsson
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Alessandro Fiorenzano
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Janitha Mudannayake
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Andreas Bruzelius
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Daniella Rylander Ottosson
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Anders Björklund
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Deirdre B Hoban
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Malin Parmar
- Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.,Lund Stem Cell Center, Lund University, Lund, Sweden
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22
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Xiao Z, Lei T, Liu Y, Yang Y, Bi W, Du H. The potential therapy with dental tissue-derived mesenchymal stem cells in Parkinson's disease. Stem Cell Res Ther 2021; 12:5. [PMID: 33407864 PMCID: PMC7789713 DOI: 10.1186/s13287-020-01957-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/27/2020] [Indexed: 12/19/2022] Open
Abstract
Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, is caused by the loss of dopaminergic (DAergic) neurons in the substantia nigra resulting in a series of motor or non-motor disorders. Current treatment methods are unable to stop the progression of PD and may bring certain side effects. Cell replacement therapy has brought new hope for the treatment of PD. Recently, human dental tissue-derived mesenchymal stem cells have received extensive attention. Currently, dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are considered to have strong potential for the treatment of these neurodegenerative diseases. These cells are considered to be ideal cell sources for the treatment of PD on account of their unique characteristics, such as neural crest origin, immune rejection, and lack of ethical issues. In this review, we briefly describe the research investigating cell therapy for PD and discuss the application and progress of DPSCs and SHED in the treatment of PD. This review offers significant and comprehensive guidance for further clinical research on PD.
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Affiliation(s)
- Zhuangzhuang Xiao
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Tong Lei
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Yanyan Liu
- Kangyanbao (Beijing) Stem Cell Technology Co., Ltd, Beijing, 102600, China
| | - Yanjie Yang
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Wangyu Bi
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Hongwu Du
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China.
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23
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The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats. Neurobiol Dis 2020; 148:105175. [PMID: 33188920 PMCID: PMC7855552 DOI: 10.1016/j.nbd.2020.105175] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 01/10/2023] Open
Abstract
Prevalent in approximately 20% of the worldwide human population, the
rs6265 (also called ‘Val66Met’) single nucleotide polymorphism
(SNP) in the gene for brain-derived neurotrophic factor (BDNF)
is a common genetic variant that can alter therapeutic responses in individuals
with Parkinson’s disease (PD). Possession of the variant Met allele
results in decreased activity-dependent release of BDNF. Given the resurgent
worldwide interest in neural transplantation for PD and the biological relevance
of BDNF, the current studies examined the effects of the rs6265 SNP on
therapeutic efficacy and side-effect development following primary dopamine (DA)
neuron transplantation. Considering the significant reduction in BDNF release
associated with rs6265, we hypothesized that rs6265-mediated dysfunctional BDNF
signaling contributes to the limited clinical benefit observed in a
subpopulation of PD patients despite robust survival of grafted DA neurons, and
further, that this mutation contributes to the development of aberrant
graft-induced dyskinesias (GID). To this end, we generated a CRISPR knock-in rat
model of the rs6265 BDNF SNP to examine for the first time the
influence of a common genetic polymorphism on graft survival, functional
efficacy, and side-effect liability, comparing these parameters between
wild-type (Val/Val) rats and those homozygous for the variant Met allele
(Met/Met). Counter to our hypothesis, the current research indicates that
Met/Met rats show enhanced graft-associated therapeutic efficacy and a
paradoxical enhancement of graft-derived neurite outgrowth compared to wild-type
rats. However, consistent with our hypothesis, we demonstrate that the rs6265
genotype in the host rat is strongly linked to development of GID, and that this
behavioral phenotype is significantly correlated with neurochemical signatures
of atypical glutamatergic neurotransmission by grafted DA neurons.
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24
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Jang SE, Qiu L, Chan LL, Tan EK, Zeng L. Current Status of Stem Cell-Derived Therapies for Parkinson's Disease: From Cell Assessment and Imaging Modalities to Clinical Trials. Front Neurosci 2020; 14:558532. [PMID: 33177975 PMCID: PMC7596695 DOI: 10.3389/fnins.2020.558532] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 09/17/2020] [Indexed: 12/23/2022] Open
Abstract
Curative therapies or treatments reversing the progression of Parkinson’s disease (PD) have attracted considerable interest in the last few decades. PD is characterized by the gradual loss of dopaminergic (DA) neurons and decreased striatal dopamine levels. Current challenges include optimizing neuroprotective strategies, developing personalized drug therapy, and minimizing side effects from the long-term prescription of pharmacological drugs used to relieve short-term motor symptoms. Transplantation of DA cells into PD patients’ brains to replace degenerated DA has the potential to change the treatment paradigm. Herein, we provide updates on current progress in stem cell-derived DA neuron transplantation as a therapeutic alternative for PD. We briefly highlight cell sources for transplantation and focus on cell assessment methods such as identification of genetic markers, single-cell sequencing, and imaging modalities used to access cell survival and function. More importantly, we summarize clinical reports of patients who have undergone cell-derived transplantation in PD to better perceive lessons that can be drawn from past and present clinical outcomes. Modifying factors include (1) source of the stem cells, (2) quality of the stem cells, (3) age of the patient, (4) stage of disease progression at the time of cell therapy, (5) surgical technique/practices, and (6) the use of immunosuppression. We await the outcomes of joint efforts in clinical trials around the world such as NYSTEM and CiRA to further guide us in the selection of the most suitable parameters for cell-based neurotransplantation in PD.
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Affiliation(s)
- Se Eun Jang
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore
| | - Lifeng Qiu
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore
| | - Ling Ling Chan
- Department of Diagnostic Radiology, Singapore General Hospital, Singapore, Singapore.,Neuroscience & Behavioral Disorders Program, Duke University and National University of Singapore (DUKE-NUS), Graduate Medical School, Singapore, Singapore
| | - Eng-King Tan
- Neuroscience & Behavioral Disorders Program, Duke University and National University of Singapore (DUKE-NUS), Graduate Medical School, Singapore, Singapore.,Department of Neurology, National Neuroscience Institute, Singapore General Hospital Campus, Singapore, Singapore
| | - Li Zeng
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore.,Neuroscience & Behavioral Disorders Program, Duke University and National University of Singapore (DUKE-NUS), Graduate Medical School, Singapore, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Novena Campus, Singapore, Singapore
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25
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Buttery PC, Barker RA. Gene and Cell-Based Therapies for Parkinson's Disease: Where Are We? Neurotherapeutics 2020; 17:1539-1562. [PMID: 33128174 PMCID: PMC7598241 DOI: 10.1007/s13311-020-00940-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that carries large health and socioeconomic burdens. Current therapies for PD are ultimately inadequate, both in terms of symptom control and in modification of disease progression. Deep brain stimulation and infusion therapies are the current mainstay for treatment of motor complications of advanced disease, but these have very significant drawbacks and offer no element of disease modification. In fact, there are currently no agents that are established to modify the course of the disease in clinical use for PD. Gene and cell therapies for PD are now being trialled in the clinic. These treatments are diverse and may have a range of niches in the management of PD. They hold great promise for improved treatment of symptoms as well as possibly slowing progression of the disease in the right patient group. Here, we review the current state of the art for these therapies and look to future strategies in this fast-moving field.
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Affiliation(s)
- Philip C Buttery
- Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, CB2 0XY, Cambridge, UK.
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Hills Road, CB2 0QQ, Cambridge, UK.
| | - Roger A Barker
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Hills Road, CB2 0QQ, Cambridge, UK.
- John van Geest Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, CB2 0PY, Cambridge, UK.
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26
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Björklund A, Parmar M. Neuronal Replacement as a Tool for Basal Ganglia Circuitry Repair: 40 Years in Perspective. Front Cell Neurosci 2020; 14:146. [PMID: 32547369 PMCID: PMC7272540 DOI: 10.3389/fncel.2020.00146] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 04/30/2020] [Indexed: 01/07/2023] Open
Abstract
The ability of new neurons to promote repair of brain circuitry depends on their capacity to re-establish afferent and efferent connections with the host. In this review article, we give an overview of past and current efforts to restore damaged connectivity in the adult mammalian brain using implants of fetal neuroblasts or stem cell-derived neuronal precursors, with a focus on strategies aimed to repair damaged basal ganglia circuitry induced by lesions that mimic the pathology seen in humans affected by Parkinson’s or Huntington’s disease. Early work performed in rodents showed that neuroblasts obtained from striatal primordia or fetal ventral mesencephalon can become anatomically and functionally integrated into lesioned striatal and nigral circuitry, establish afferent and efferent connections with the lesioned host, and reverse the lesion-induced behavioral impairments. Recent progress in the generation of striatal and nigral progenitors from pluripotent stem cells have provided compelling evidence that they can survive and mature in the lesioned brain and re-establish afferent and efferent axonal connectivity with a remarkable degree of specificity. The studies of cell-based circuitry repair are now entering a new phase. The introduction of genetic and virus-based techniques for brain connectomics has opened entirely new possibilities for studies of graft-host integration and connectivity, and the access to more refined experimental techniques, such as chemo- and optogenetics, has provided new powerful tools to study the capacity of grafted neurons to impact the function of the host brain. Progress in this field will help to guide the efforts to develop therapeutic strategies for cell-based repair in Huntington’s and Parkinson’s disease and other neurodegenerative conditions involving damage to basal ganglia circuitry.
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Affiliation(s)
- Anders Björklund
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
| | - Malin Parmar
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
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27
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Safari F, Hatam G, Behbahani AB, Rezaei V, Barekati-Mowahed M, Petramfar P, Khademi F. CRISPR System: A High-throughput Toolbox for Research and Treatment of Parkinson's Disease. Cell Mol Neurobiol 2020; 40:477-493. [PMID: 31773362 PMCID: PMC11448816 DOI: 10.1007/s10571-019-00761-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/14/2019] [Indexed: 12/13/2022]
Abstract
In recent years, the innovation of gene-editing tools such as the CRISPR/Cas9 system improves the translational gap of treatments mediated by gene therapy. The privileges of CRISPR/Cas9 such as working in living cells and organs candidate this technology for using in research and treatment of the central nervous system (CNS) disorders. Parkinson's disease (PD) is a common, debilitating, neurodegenerative disorder which occurs due to loss of dopaminergic neurons and is associated with progressive motor dysfunction. Knowledge about the pathophysiological basis of PD has altered the classification system of PD, which manifests in familial and sporadic forms. The first genetic linkage studies in PD demonstrated the involvement of Synuclein alpha (SNCA) mutations and SNCA genomic duplications in the pathogenesis of PD familial forms. Subsequent studies have also insinuated mutations in leucine repeat kinase-2 (LRRK2), Parkin, PTEN-induced putative kinase 1 (PINK1), as well as DJ-1 causing familial forms of PD. This review will attempt to discuss the structure, function, and development in genome editing mediated by CRISP/Cas9 system. Further, it describes the genes involved in the pathogenesis of PD and the pertinent alterations to them. We will pursue this line by delineating the PD linkage studies in which CRISPR system was employed. Finally, we will discuss the pros and cons of CRISPR employment vis-à-vis the process of genome editing in PD patients' iPSCs.
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Affiliation(s)
- Fatemeh Safari
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholamreza Hatam
- Basic Sciences in Infectious Diseases Research Center, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Behzad Behbahani
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahid Rezaei
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazyar Barekati-Mowahed
- Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, Ohio, USA
| | - Peyman Petramfar
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Khademi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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28
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Precious SV, Smith GA, Heuer A, Jaeger I, Lane EL, Dunnett SB, Li M, Kelly CM, Rosser AE. Dopaminergic Progenitors Derived From Epiblast Stem Cells Function Similarly to Primary VM-Derived Progenitors When Transplanted Into a Parkinson's Disease Model. Front Neurosci 2020; 14:312. [PMID: 32317925 PMCID: PMC7154167 DOI: 10.3389/fnins.2020.00312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 03/17/2020] [Indexed: 11/13/2022] Open
Abstract
Neural transplantation in neurodegenerative diseases such as Parkinson’s disease (PD) offers to replace cells lost during the progression of the disease process. Primary fetal ventral mesencephalon (VM), the origin of bona fide midbrain dopaminergic (DAergic) precursors, is currently the gold standard source of cells for transplantation in PD. However, the use of tissue from this source raises ethical and logistical constraints necessitating the need for alternative supplies of donor cells. The requirement of any alternative donor cell source is to have the capability to generate authentic mature DAergic neurons, which could be utilized in cell-replacement strategies. Mouse pluripotent stem cells can efficiently generate electrochemically mature midbrain DAergic precursors in vitro using a stepwise control of FGF signaling. Here, we have compared DAergic transplants derived from two progenitor cell sources in an allograft system: mouse epiblast stem cells (EpiSC) and primary fetal mouse VM tissue. Cells were transplanted into the striatum of 6-OHDA lesioned mice pre-treated with L-DOPA. Drug-induced rotations, a number of motor tests and drug-induced abnormal involuntary movements (AIMs) were assessed. Functional improvements were demonstrated post-transplantation in some behavioral tests, with no difference in graft volume or the number of TH immuno-positive cells in the grafts of the two transplant groups. L-DOPA-induced AIMs and amphetamine-induced AIMs were observed in both transplant groups, with no differences in rate or severity between the two groups. Collectively, in this mouse-to-mouse allograft system, we report no significant differences in the functional ability between the gold standard primary VM derived and pluripotent stem cell-derived DAergic transplants.
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Affiliation(s)
- Sophie V Precious
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Gaynor A Smith
- School of Medicine, UK Dementia Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Andreas Heuer
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.,Behavioural Neuroscience Laboratory, Department of Experimental Medical Sciences, Lund University, Lund, Sweden
| | - Ines Jaeger
- Stem Cell Neurogenesis Group, School of Medicine and Biosciences, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Emma L Lane
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom
| | - Stephen B Dunnett
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Meng Li
- Stem Cell Neurogenesis Group, School of Medicine and Biosciences, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Claire M Kelly
- School of Health Sciences, Cardiff Metropolitan University, Cardiff, United Kingdom
| | - Anne E Rosser
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.,Wales Brain Repair and Intracranial Neurotherapeutics Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom.,MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom
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29
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Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease. Cell Stem Cell 2020; 26:511-526.e5. [PMID: 32059808 DOI: 10.1016/j.stem.2020.01.010] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/31/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022]
Abstract
Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.
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30
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Zhao D, Li YH, Yang ZY, Cai T, Wu XY, Xia Y, Zhou Z. [Effect of the local application of stem cells on repairing facial nerve defects: a systematic review]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2020; 38:59-68. [PMID: 32037768 DOI: 10.7518/hxkq.2020.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
OBJECTIVE To systematically evaluate the repairing effect of stem cells on facial nerve defects. METHODS Articles regarding the regenerating effect of stem cells on facial nerves in animals were collected from the databases of Pubmed, Cochrane Library, Web of Science, Embase, Scopus, and CBM. Two professionals independently completed the article screening, data extraction, and bias risk assessment. RevMan 5.3 and random-effects models were used for the statistical analysis, and the results were presented in the form of mean differences (MD) with a 95%CI. The results of functional evaluation (vibrissae movement, facial paralysis) and histological evaluation (density of myelinated fibers, diameter of fibers, thickness of myelin sheath, G ratio) of facial nerve were Meta-analyzed. RESULTS A total of 4 614 articles were retrieved from the 6 databases, and 15 of these articles were included in the Meta-analysis. For vibrissae movement and facial paralysis, the stem cell group scored significantly higher than the non-stem cell group (P<0.05). The density of myelinated fibers and thickness of the myelin sheath in the stem cell group were higher than those in the non-stem cell group (P<0.05). The G ratio in the stem cell group was smaller than that in the non-stem cell group (P=0.001). There was no significant difference in fiber diameter (P=0.08). CONCLUSIONS Stem cells have potential in promoting facial nerve regeneration.
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Affiliation(s)
- Dan Zhao
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
| | - Yue-Heng Li
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
| | - Zheng-Yan Yang
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
| | - Ting Cai
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
| | - Xiao-Yan Wu
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
| | - Yu Xia
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
| | - Zhi Zhou
- Dept. of Preventive Stomatology, Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Muni-cipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401120, China
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31
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Fan Y, Winanto, Ng SY. Replacing what's lost: a new era of stem cell therapy for Parkinson's disease. Transl Neurodegener 2020; 9:2. [PMID: 31911835 PMCID: PMC6945567 DOI: 10.1186/s40035-019-0180-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/26/2019] [Indexed: 12/31/2022] Open
Abstract
Background Stem cells hold tremendous promise for regenerative medicine because they can be expanded infinitely, giving rise to large numbers of differentiated cells required for transplantation. Stem cells can be derived from fetal sources, embryonic origins (embryonic stem cells or ESCs) or reprogrammed from adult cell types (induced pluripotent stem cells or iPSCs). One unique property of stem cells is their ability to be directed towards specific cell types of clinical interest, and can mature into functional cell types in vivo. While transplantations of fetal or ESC-derived tissues are known to illicit a host immunogenic response, autologous transplantations using cell types derived from one’s own iPSCs eliminate risks of tissue rejection and reduce the need for immunosuppressants. However, even with these benefits, cell therapy comes with significant hurdles that researchers are starting to overcome. In this review, we will discuss the various steps to ensure safety, efficacy and clinical practicality of cell replacement therapy in neurodegenerative diseases, in particular, Parkinson’s disease. Main body Parkinson’s disease (PD) results from a loss of dopaminergic neurons from the substantia nigra and is an ideal target for cell replacement therapy. Early trials using fetal midbrain material in the late 1980s have resulted in long term benefit for some patients, but there were multiple shortcomings including the non-standardization and quality control of the transplanted fetal material, and graft-induced dyskinesia that some patients experience as a result. On the other hand, pluripotent stem cells such as ESCs and iPSCs serve as an attractive source of cells because they can be indefinitely cultured and is an unlimited source of cells. Stem cell technologies and our understanding of the developmental potential of ESCs and iPSCs have deepened in recent years and a clinical trial for iPSC-derived dopaminergic cells is currently undergoing for PD patients in Japan. In this focused review, we will first provide a historical aspect of cell therapies in PD, and then discuss the various challenges pertaining to the safety and efficacy of stem cell-based cell transplantations, and how these hurdles were eventually overcome. Conclusion With the maturity of the iPSC technology, cell transplantation appears to be a safe and effective therapy. Grafts in non-human primates survive and remain functional for more than 2 years after transplantation, with no signs of tumorigenesis, indicating safety and efficacy of the treatment. However, immunosuppressants are still required because of the lack of “universal stem cells” that would not evoke an immune response. The results of ongoing and upcoming trials by a global consortium known as GForce-PD would be highly anticipated because the success of these trials would open up possibilities for using cell therapy for the treatment of PD and other degenerative diseases.
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Affiliation(s)
- Yong Fan
- 1The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150 China
| | - Winanto
- 2Institute of Molecular and Cell Biology, ASTAR Research Entities, Singapore, 138673 Singapore
| | - Shi-Yan Ng
- 1The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150 China.,2Institute of Molecular and Cell Biology, ASTAR Research Entities, Singapore, 138673 Singapore.,3Yong Loo Lin School of Medicine (Physiology), National University of Singapore, Singapore, 117456 Singapore.,4National Neuroscience Institute, Singapore, 308433 Singapore
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Wang Z, Zheng Y, Zheng M, Zhong J, Ma F, Zhou B, Zhu J. Neurogenic Niche Conversion Strategy Induces Migration and Functional Neuronal Differentiation of Neural Precursor Cells Following Brain Injury. Stem Cells Dev 2020; 29:235-248. [PMID: 31797735 DOI: 10.1089/scd.2019.0147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glial scars formed after brain injuries provide permissive cues for endogenous neural precursor/stem cells (eNP/SCs) to undergo astrogenesis rather than neurogenesis. Following brain injury, eNP/SCs from the subventricular zone leave their niche, migrate to the injured cortex, and differentiate into reactive astrocytes that contribute to glial scar formation. In vivo neuronal reprogramming, directly converting non-neuronal cells such as reactive astrocytes or NG2 glia into neurons, has greatly improved brain injury repair strategies. However, reprogramming carries a high risk of future clinical applications such as tumorigenicity, involving virus. In this study, we constructed a neural matrix to alter the adverse niche at the injured cortex, enabling eNP/SCs to differentiate into functional neurons. We found that the neural matrix functioned as a "glial trap" that largely concentrated and limited reactive astrocytes to the core of the lesion area, thus altering the adverse niche. The eNP/SCs migrated toward the injured cortex and differentiated into functional neurons. In addition, regenerated neurites extended across the boundary of the injured cortex. Mice treated with the neural matrix demonstrated significant behavioral recovery. For the first time, we induced eNP/SC-derived functional neurons in the cortex after brain injury without the use of viruses, microRNAs, or small molecules. Our novel strategy of applying this "glial trap" to obtain functional neurons in the injured cortex may provide a safer and more natural therapeutic alternative to reprogramming in future clinical applications.
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Affiliation(s)
- Zhifu Wang
- Department of Neurosurgery, Huashan Hospital and National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yongtao Zheng
- Department of Neurosurgery, Huashan Hospital and National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mingzhe Zheng
- Department of Neurosurgery, Huashan Hospital and National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Junjie Zhong
- Department of Neurosurgery, Huashan Hospital and National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fukai Ma
- Department of Neurosurgery, Huashan Hospital and National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.,Neurosurgery Department, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Bin Zhou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (CAS), University of Chinese Academy of Sciences, Shanghai, China
| | - Jianhong Zhu
- Department of Neurosurgery, Huashan Hospital and National Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
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33
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Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci 2020; 21:103-115. [DOI: 10.1038/s41583-019-0257-7] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2019] [Indexed: 01/07/2023]
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Cendelin J, Buffo A, Hirai H, Magrassi L, Mitoma H, Sherrard R, Vozeh F, Manto M. Task Force Paper On Cerebellar Transplantation: Are We Ready to Treat Cerebellar Disorders with Cell Therapy? THE CEREBELLUM 2019; 18:575-592. [PMID: 30607797 DOI: 10.1007/s12311-018-0999-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.
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Affiliation(s)
- Jan Cendelin
- Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
- Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
| | - Annalisa Buffo
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, 10126, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, 10043, Turin, Italy
| | - Hirokazu Hirai
- Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan
| | - Lorenzo Magrassi
- Neurosurgery, Dipartimento di Scienze Clinico-Chirurgiche Diagnostiche e Pediatriche, Fondazione IRCCS Policlinico S. Matteo, Università degli Studi di Pavia, 27100, Pavia, Italy
- Istituto di Genetica Molecolare - CNR, 27100, Pavia, Italy
| | - Hiroshi Mitoma
- Medical Education Promotion Center, Tokyo Medical University, Tokyo, Japan
| | - Rachel Sherrard
- IBPS, UMR8256 Biological Adaptation and Ageing, Sorbonne Université and CNRS, Paris, France
| | - Frantisek Vozeh
- Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
- Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody 1655/76, 323 00, Plzen, Czech Republic
| | - Mario Manto
- Department of Neurology, CHU-Charleroi, 6000, Charleroi, Belgium.
- Service des Neurosciences, Université de Mons, 7000, Mons, Belgium.
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35
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Collier TJ, Sortwell CE, Mercado NM, Steece‐Collier K. Cell therapy for Parkinson's disease: Why it doesn't work every time. Mov Disord 2019; 34:1120-1127. [PMID: 31234239 PMCID: PMC6771700 DOI: 10.1002/mds.27742] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 05/08/2019] [Accepted: 05/20/2019] [Indexed: 11/29/2022] Open
Abstract
The clinical experience with cell replacement therapy for advanced PD has yielded notable successes and failures. A recent autopsy case report of an individual that received implants of fetal dopamine neurons 16 years previously, but at no time experienced clinical benefit despite the best documented survival of grafted neurons and most extensive reinnervation of the striatum, raises sobering issues. With good reason, a great deal of effort in cell replacement science continues to focus on optimizing the cell source and implantation procedure. Here, we describe our preclinical studies in aged rats indicating that despite survival of large numbers of transplanted dopamine neurons and dense reinnervation of the striatum, synaptic connections between graft and host are markedly decreased and behavioral recovery is impaired. This leads us to the hypothesis that the variability in therapeutic response to dopamine neuron grafts may be less about the viability of transplanted neurons and more about the integrity of the aged, dopamine-depleted striatum and its capacity for repair. Replacement of dopamine innervation only can be fully effective if the correct target is present. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Timothy J. Collier
- Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA, and Hauenstein Neuroscience CenterMercy Health/St. Mary'sGrand RapidsMichiganUSA
| | - Caryl E. Sortwell
- Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA, and Hauenstein Neuroscience CenterMercy Health/St. Mary'sGrand RapidsMichiganUSA
| | - Natosha M. Mercado
- Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA, and Hauenstein Neuroscience CenterMercy Health/St. Mary'sGrand RapidsMichiganUSA
| | - Kathy Steece‐Collier
- Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA, and Hauenstein Neuroscience CenterMercy Health/St. Mary'sGrand RapidsMichiganUSA
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36
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Barker RA. Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease. Nat Med 2019; 25:1045-1053. [PMID: 31263283 DOI: 10.1038/s41591-019-0507-2] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 06/03/2019] [Indexed: 02/07/2023]
Abstract
Clinical studies of Parkinson's disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO ( NCT01898390 ), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
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Affiliation(s)
- Roger A Barker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences and WT-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
- John van Geest Centre for Brain Repair, Cambridge University, Cambridge, UK.
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37
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Simorgh S, Alizadeh R, Eftekharzadeh M, Haramshahi SMA, Milan PB, Doshmanziari M, Ramezanpour F, Gholipourmalekabadi M, Seifi M, Moradi F. Olfactory mucosa stem cells: An available candidate for the treatment of the Parkinson's disease. J Cell Physiol 2019; 234:23763-23773. [PMID: 31173364 DOI: 10.1002/jcp.28944] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 01/01/2023]
Abstract
Olfactory ectomesenchymal stem cells (OE-MSCs) possess the immunosuppressive activity and regeneration capacity and hold a lot of promises for neurodegenerative disorders treatment. This study aimed to determine OE-MSCs which are able to augment and differentiate into functional neurons and regenerate the CNS and also examine whether the implantation of OE-MSCs in the pars compacta of the substantia nigra (SNpc) can improve Parkinson's symptoms in a rat model-induced with 6-hydroxydopamine. We isolated OE-MSCs from lamina propria in olfactory mucosa and characterized them using flow cytometry and immunocytochemistry. The therapeutic potential of OE-MSCs was evaluated by the transplantation of isolated cells using a rat model of acute SN injury as a Parkinson's disease. Significant behavioral improvement in Parkinsonian rats was elicited by the OE-MSCs. The results demonstrate that the expression of PAX2, PAX5, PITX3, dopamine transporter, and tyrosine hydroxylase was increased by OE-MSCs compared to the control group which is analyzed with real-time polymerase chain reaction technique and immunohistochemical staining. In the outcome, the transplantation of 1,1'-dioctadecyl-3,3,3'3'-tetramethyl indocarbocyanine perchlorate labeled OE-MSCs that were fully differentiated to dopaminergic neurons contribute to a substantial improvement in patients with Parkinson's. Together, our results provide that using OE-MSCs in neurodegenerative disorders might lead to better neural regeneration.
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Affiliation(s)
- Sara Simorgh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rafieh Alizadeh
- ENT and Head & Neck Research Center and Department, The Five Senses Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mina Eftekharzadeh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Haramshahi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Doshmanziari
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farnaz Ramezanpour
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Morteza Seifi
- Departments of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Fatemeh Moradi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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38
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Abstract
Cell therapy for Parkinson's disease has a history of being applied clinically with aborted embryos as donor source. Efficacy of the therapy under the appropriate condition has been reported. Based on this experience and the advancement of stem cell technology, clinical trials of cell therapy with embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) are going to start soon in several countries. In Japan a physician-initiated clinical trial of iPSC-based therapy for Parkinson's disease has launched since 2018. This trial adopts allogeneic transplantation with a cell line from iPSC stock. This article discusses patient selection, procedure, and risk of the therapy. It also introduces the world's current situation of the cell therapy for Parkinson's disease.
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Affiliation(s)
- Asuka Morizane
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University
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39
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Chen Y, Dolt KS, Kriek M, Baker T, Downey P, Drummond NJ, Canham MA, Natalwala A, Rosser S, Kunath T. Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene. Eur J Neurosci 2019; 49:510-524. [PMID: 30472757 PMCID: PMC6492083 DOI: 10.1111/ejn.14286] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 11/12/2018] [Accepted: 11/16/2018] [Indexed: 01/09/2023]
Abstract
An emerging treatment for Parkinson's disease (PD) is cell replacement therapy. Authentic midbrain dopaminergic (mDA) neuronal precursors can be differentiated from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). These laboratory-generated mDA cells have been demonstrated to mature into functional dopaminergic neurons upon transplantation into preclinical models of PD. However, clinical trials with human fetal mesenchephalic cells have shown that cell replacement grafts in PD are susceptible to Lewy body formation suggesting host-to-graft transfer of α-synuclein pathology. Here, we have used CRISPR/Cas9n technology to delete the endogenous SNCA gene, encoding for α-synuclein, in a clinical-grade hESC line to generate SNCA+/- and SNCA-/- cell lines. These hESC lines were first differentiated into mDA neurons, and then challenged with recombinant α-synuclein preformed fibrils (PFFs) to seed the formation for Lewy-like pathology as measured by phosphorylation of serine-129 of α-synuclein (pS129-αSyn). Wild-type neurons were fully susceptible to the formation of protein aggregates positive for pS129-αSyn, while SNCA+/- and SNCA-/- neurons exhibited significant resistance to the formation of this pathological mark. This work demonstrates that reducing or completely removing SNCA alleles by CRISPR/Cas9n-mediated gene editing confers a measure of resistance to Lewy pathology.
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Affiliation(s)
- Yixi Chen
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
- UK Centre for Mammalian Synthetic BiologyThe University of EdinburghEdinburghUK
| | - Karamjit Singh Dolt
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | | | | | | | - Nicola J. Drummond
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | - Maurice A. Canham
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | - Ammar Natalwala
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | - Susan Rosser
- UK Centre for Mammalian Synthetic BiologyThe University of EdinburghEdinburghUK
| | - Tilo Kunath
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
- UK Centre for Mammalian Synthetic BiologyThe University of EdinburghEdinburghUK
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40
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Kunath T, Natalwala A, Chan C, Chen Y, Stecher B, Taylor M, Khan S, Muqit MMK. Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies? Eur J Neurosci 2019; 49:453-462. [PMID: 30586214 PMCID: PMC6492143 DOI: 10.1111/ejn.14314] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 11/29/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022]
Abstract
Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow progressing and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy.
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Affiliation(s)
- Tilo Kunath
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | - Ammar Natalwala
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
- Translational Neurosurgery GroupWestern General HospitalEdinburghUK
| | - Claire Chan
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | - Yixi Chen
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesThe University of EdinburghEdinburghUK
| | | | - Martin Taylor
- Edinburgh Research Interest GroupParkinson's UKEdinburghUK
| | - Sadaquate Khan
- Translational Neurosurgery GroupWestern General HospitalEdinburghUK
| | - Miratul M. K. Muqit
- MRC Protein Phosphorylation and Ubiquitylation UnitSchool of Life SciencesUniversity of DundeeDD1 5EHDundeeUK
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41
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Deciduous DPSCs Ameliorate MPTP-Mediated Neurotoxicity, Sensorimotor Coordination and Olfactory Function in Parkinsonian Mice. Int J Mol Sci 2019; 20:ijms20030568. [PMID: 30699944 PMCID: PMC6387212 DOI: 10.3390/ijms20030568] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 01/20/2019] [Accepted: 01/23/2019] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder defined by progressive deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dental pulp stem cells (DPSCs) have been proposed to replace the degenerated dopaminergic neurons due to its inherent neurogenic and regenerative potential. However, the effective delivery and homing of DPSCs within the lesioned brain has been one of the many obstacles faced in cell-based therapy of neurodegenerative disorders. We hypothesized that DPSCs, delivered intranasally, could circumvent these challenges. In the present study, we investigated the therapeutic efficacy of intranasally administered DPSCs in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Human deciduous DPSCs were cultured, pre-labelled with PKH 26, and intranasally delivered into PD mice following MPTP treatment. Behavioural analyses were performed to measure olfactory function and sensorimotor coordination, while tyrosine hydroxylase (TH) immunofluorescence was used to evaluate MPTP neurotoxicity in SNpc neurons. Upon intranasal delivery, degenerated TH-positive neurons were ameliorated, while deterioration in behavioural performances was significantly enhanced. Thus, the intranasal approach enriched cell delivery to the brain, optimizing its therapeutic potential through its efficacious delivery and protection against dopaminergic neuron degeneration.
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42
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Stem Cell Transplantation and Physical Exercise in Parkinson's Disease, a Literature Review of Human and Animal Studies. Stem Cell Rev Rep 2018; 14:166-176. [PMID: 29270820 DOI: 10.1007/s12015-017-9798-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The absence of effective and satisfactory treatments that contribute to repairing the dopaminergic damage caused by Parkinson's Disease (PD) and the limited recovery capacity of the nervous system are troubling issues and the focus of many research and clinical domains. Recent advances in the treatment of PD through stem cell (SC) therapy have recognized their promising restorative and neuroprotective effects that are implicated in the potentiation of endogenous mechanisms of repair and contribute to functional locomotor improvement. Physical exercise (PE) has been considered an adjuvant intervention that by itself induces beneficial effects in patients and animal models with Parkinsonism. In this sense, the combination of both therapies could provide synergic or superior effects for motor recovery, in contrast with their individual use. This review aims to provide an update on recent progress and the potential effectiveness of SC transplantation and PE for the treatment of locomotor deficits in PD. It has reviewed the neuropathological pathways involved in the classical motor symptoms of this condition and the mechanisms of action described in experimental studies that are associated with locomotor enhancement through exercise, cellular transplantation, and their union in some neurodegenerative conditions.
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43
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de Natale ER, Wilson H, Pagano G, Politis M. Imaging Transplantation in Movement Disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 143:213-263. [PMID: 30473196 DOI: 10.1016/bs.irn.2018.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cell replacement therapy with graft transplantation has been tested as a disease-modifying treatment in neurodegenerative diseases characterized by the damage of a predominant cell type, such as substantia nigra dopaminergic neurons in Parkinson's disease (PD) or striatal medium spiny projection neurons in Huntington's disease (HD). The results of these trials are mixed with success in preclinical and pilot open-label trials, which were not consistently reproduced in randomized controlled trials. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) molecular imaging and functional magnetic resonance imaging allow the graft survival, and its relationship with the host tissues to be studied in vivo. In PD, PET with [18F]DOPA showed that graft survival does not necessarily correlate with the clinical improvement and PD patients with worse outcome had lower binding in the ventral striatum and a high serotonin ([11C]DASB PET) to dopamine ([18F]DOPA PET) ratio in the grafted neurons. In HD, PET with [11C]PK11195 showed the graft survival and the clinical responses may be related to the reactive activation of the host inflammatory/immune system. Findings from these studies have been used to refine study protocols and patient selection in current clinical trials, which includes identifying suitable candidates for transplantation using imaging markers and employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts.
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Affiliation(s)
- Edoardo Rosario de Natale
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Heather Wilson
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Gennaro Pagano
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Marios Politis
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
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Sonntag KC, Song B, Lee N, Jung JH, Cha Y, Leblanc P, Neff C, Kong SW, Carter BS, Schweitzer J, Kim KS. Pluripotent stem cell-based therapy for Parkinson's disease: Current status and future prospects. Prog Neurobiol 2018; 168:1-20. [PMID: 29653250 PMCID: PMC6077089 DOI: 10.1016/j.pneurobio.2018.04.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 03/13/2018] [Accepted: 04/05/2018] [Indexed: 12/11/2022]
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects about 0.3% of the general population. As the population in the developed world ages, this creates an escalating burden on society both in economic terms and in quality of life for these patients and for the families that support them. Although currently available pharmacological or surgical treatments may significantly improve the quality of life of many patients with PD, these are symptomatic treatments that do not slow or stop the progressive course of the disease. Because motor impairments in PD largely result from loss of midbrain dopamine neurons in the substantia nigra pars compacta, PD has long been considered to be one of the most promising target diseases for cell-based therapy. Indeed, numerous clinical and preclinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells as a standardized therapeutic regimen has been fraught with fundamental ethical, practical, and clinical issues, prompting scientists to explore alternative cell sources. Based on groundbreaking establishments of human embryonic stem cells and induced pluripotent stem cells, these human pluripotent stem cells have been the subject of extensive research, leading to tremendous advancement in our understanding of these novel classes of stem cells and promising great potential for regenerative medicine. In this review, we discuss the prospects and challenges of human pluripotent stem cell-based cell therapy for PD.
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Affiliation(s)
- Kai-C Sonntag
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Laboratory for Translational Research on Neurodegeneration, 115 Mill Street, Belmont, MA, 02478, United States; Program for Neuropsychiatric Research, 115 Mill Street, Belmont, MA, 02478, United States
| | - Bin Song
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Nayeon Lee
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Jin Hyuk Jung
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Young Cha
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Pierre Leblanc
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States
| | - Carolyn Neff
- Kaiser Permanente Medical Group, Irvine, CA, 92618, United States
| | - Sek Won Kong
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, United States; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, 02115, United States
| | - Bob S Carter
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, 02114, United States
| | - Jeffrey Schweitzer
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, 02114, United States.
| | - Kwang-Soo Kim
- Department of Psychiatry, McLean Hospital, Harvard Medical School, United States; Molecular Neurobiology Laboratory, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, United States.
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Cell reprogramming approaches in gene- and cell-based therapies for Parkinson's disease. J Control Release 2018; 286:114-124. [PMID: 30026082 DOI: 10.1016/j.jconrel.2018.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 12/17/2022]
Abstract
Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta is the pathological hallmark of Parkinson's disease (PD). In PD multiple pathogenic mechanisms initiate and drive this neurodegenerative process, making the development of effective treatments challenging. To date, PD patients are primarily treated with dopaminergic drugs able to temporarily enhance DA levels, therefore relieving motor symptoms. However, the drawbacks of these therapies including the inability to alter disease progression are constantly supporting the search for alternative treatment approaches. Over the past years efforts have been put into the development of new therapeutic strategies based on the delivery of therapeutic genes using viral vectors or transplantation of DA neurons for cell-based DA replacement. Here, past achievements and recent advances in gene- and cell-based therapies for PD are outlined. We discuss how current gene and cell therapy strategies hold great promise for the treatment of PD and how the use of stem cells and recent developments in cellular reprogramming could contribute to open a new avenue in PD therapy.
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Moriarty N, Parish CL, Dowd E. Primary tissue for cellular brain repair in Parkinson's disease: Promise, problems and the potential of biomaterials. Eur J Neurosci 2018; 49:472-486. [PMID: 29923311 DOI: 10.1111/ejn.14051] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/06/2018] [Accepted: 06/12/2018] [Indexed: 12/19/2022]
Abstract
The dopamine precursor, levodopa, remains the "gold standard" treatment for Parkinson's disease, and, although it provides superlative efficacy in the early stages of the disease, its long-term use is limited by the development of severe motor side effects and a significant abating of therapeutic efficacy. Therefore, there remains a major unmet clinical need for the development of effective neuroprotective, neurorestorative or neuroreparatory therapies for this condition. The relatively selective loss of dopaminergic neurons from the nigrostriatal pathway makes Parkinson's disease an ideal candidate for reparative cell therapies, wherein the dopaminergic neurons that are lost in the condition are replaced through direct cell transplantation into the brain. To date, this approach has been developed, validated and clinically assessed using dopamine neuron-rich foetal ventral mesencephalon grafts which have been shown to survive and reinnervate the denervated brain after transplantation, and to restore motor function. However, despite long-term symptomatic relief in some patients, significant limitations, including poor graft survival and the impact this has on the number of foetal donors required, have prevented this therapy being more widely adopted as a restorative approach for Parkinson's disease. Injectable biomaterial scaffolds have the potential to improve the delivery, engraftment and survival of these grafts in the brain through provision of a supportive microenvironment for cell adhesion, growth and immune shielding. This article will briefly review the development of primary cell therapies for brain repair in Parkinson's disease and will consider the emerging literature which highlights the potential of using injectable biomaterial hydrogels in this context.
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Affiliation(s)
- Niamh Moriarty
- Pharmacology & Therapeutics and Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland
| | - Clare L Parish
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Eilís Dowd
- Pharmacology & Therapeutics and Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland
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Pang AL, Xiong LL, Xia QJ, Liu F, Wang YC, Liu F, Zhang P, Meng BL, Tan S, Wang TH. Neural Stem Cell Transplantation Is Associated with Inhibition of Apoptosis, Bcl-xL Upregulation, and Recovery of Neurological Function in a Rat Model of Traumatic Brain Injury. Cell Transplant 2018; 26:1262-1275. [PMID: 28933221 PMCID: PMC5657736 DOI: 10.1177/0963689717715168] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Traumatic brain injury (TBI) is a common disease that usually causes severe neurological damage, and current treatment is far from satisfactory. The neuroprotective effects of neural stem cell (NSC) transplantation in the injured nervous system have largely been known, but the underlying mechanisms remain unclear, and their limited sources impede their clinical application. Here, we established a rat model of TBI by dropping a weight onto the cortical motor area of the brain and explored the effect of engrafted NSCs (passage 3, derived from the hippocampus of embryonic 12- to 14-d green fluorescent protein transgenic mice) on TBI rats. Moreover, RT-PCR and Western blotting were employed to investigate the possible mechanism associated with NSC grafts. We found rats with TBI exhibited a severe motor and equilibrium dysfunction, while NSC transplantation could partly improve the motor function and significantly reduce cell apoptosis and increase B-cell lymphoma–extra large (Bcl-xL) expression at 7 d postoperation. However, other genes including Bax, B-cell lymphoma 2, Fas ligand, and caspase3 did not exhibit significant differences in expression. Moreover, to test whether Bcl-xL could be used as a therapeutic target, herpes simplex virus (HSV) 1 carrying Bcl-xL recombinant was constructed and injected into the pericontusional cortices. Bcl-xL overexpression not only resulted in a significant improvement in neurological function but also inhibits cell apoptosis, as compared with the TBI rats, and exhibits the same effects as the administration of NSC. The present study therefore indicated that NSC transplantation could promote the recovery of TBI rats in a manner similar to that of Bcl-xL overexpression. Therefore, Bcl-xL overexpression, to some extent, could be considered as a useful strategy to replace NSC grafting in the treatment of TBI in future clinical practices.
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Affiliation(s)
- Ai-Lan Pang
- 1 Department of Neurology, Zhujiang Hospital Southern Medical University, Guangzhou, Guangdong, China.,4 Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Liu-Lin Xiong
- 3 Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qing-Jie Xia
- 3 Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fen Liu
- 3 Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - You-Cui Wang
- 3 Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fei Liu
- 3 Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
| | - Piao Zhang
- 2 Institute of Neuroscience, Kunming Medical University, Kunming, China
| | - Bu-Liang Meng
- 5 Department of Human Anatomy Histology and Embryology, Kunming Medical University, Kunming, China
| | - Sheng Tan
- 1 Department of Neurology, Zhujiang Hospital Southern Medical University, Guangzhou, Guangdong, China
| | - Ting-Hua Wang
- 2 Institute of Neuroscience, Kunming Medical University, Kunming, China.,3 Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
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Zenchak JR, Palmateer B, Dorka N, Brown TM, Wagner LM, Medendorp WE, Petersen ED, Prakash M, Hochgeschwender U. Bioluminescence-driven optogenetic activation of transplanted neural precursor cells improves motor deficits in a Parkinson's disease mouse model. J Neurosci Res 2018; 98:458-468. [PMID: 29577367 DOI: 10.1002/jnr.24237] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 02/21/2018] [Accepted: 03/08/2018] [Indexed: 12/21/2022]
Abstract
The need to develop efficient therapies for neurodegenerative diseases is urgent, especially given the increasing percentages of the population living longer, with increasing chances of being afflicted with conditions like Parkinson's disease (PD). A promising curative approach toward PD and other neurodegenerative diseases is the transplantation of stem cells to halt and potentially reverse neuronal degeneration. However, stem cell therapy does not consistently lead to improvement for patients. Using remote stimulation to optogenetically activate transplanted cells, we attempted to improve behavioral outcomes of stem cell transplantation. We generated a neuronal precursor cell line expressing luminopsin 3 (LMO3), a luciferase-channelrhodopsin fusion protein, which responds to the luciferase substrate coelenterazine (CTZ) with emission of blue light that in turn activates the opsin. Neuronal precursor cells were injected bilaterally into the striatum of homozygous aphakia mice, which carry a spontaneous mutation leading to lack of dopaminergic neurons and symptoms of PD. Following transplantation, the cells were stimulated over a period of 10 days by intraventricular injections of CTZ. Mice receiving CTZ demonstrated significantly improved motor skills in a rotarod test compared to mice receiving vehicle. Thus, bioluminescent optogenetic stimulation of transplanted neuronal precursor cells shows promising effects in improving locomotor behavior in the aphakia PD mouse model and encourages further studies to elucidate the mechanisms and long-term outcomes of these beneficial effects.
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Affiliation(s)
- Jessica R Zenchak
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan.,College of Medicine, Central Michigan University, Mt. Pleasant, Michigan
| | - Brandon Palmateer
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan
| | - Nicolai Dorka
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan
| | - Tariq M Brown
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan
| | - Lina-Marie Wagner
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan
| | | | - Eric D Petersen
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan
| | - Mansi Prakash
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan.,College of Medicine, Central Michigan University, Mt. Pleasant, Michigan
| | - Ute Hochgeschwender
- Neuroscience Program, Central Michigan University, Mt. Pleasant, Michigan.,College of Medicine, Central Michigan University, Mt. Pleasant, Michigan
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Abstract
Neurotransplantation may be a promising approach for therapy of cerebellar diseases characterized by a substantial loss of neurons. Neurotransplantation could rescue neurons from degeneration and maintain cerebellar reserve, facilitate cerebellar compensation, or help reconstruct damaged neural circuits by cell substitution. These mechanisms of action can be of varying importance according to the type of cerebellar disease. Neurotransplantation therapy in cerebellar ataxias is still at the stage of experimental studies. There is currently little knowledge regarding cerebellar patients. Nevertheless, data provided by experiments in animal models of cerebellar degeneration and both clinical studies and experiences in patients with other neurologic diseases enable us to suggest basic principles, expectations, limitations, and future directions of neurotransplantation therapy for cerebellar diseases.
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Affiliation(s)
- Jan Cendelin
- Department of Pathological Physiology and Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine, Charles University, Pilsen, Czech Republic.
| | - Hiroshi Mitoma
- Department of Medical Education, Tokyo Medical University, Tokyo, Japan
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50
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Ku J, El-Hashash A. Stem Cell Roles and Applications in Genetic Neurodegenerative Diseases. STEM CELLS IN CLINICAL APPLICATIONS 2018. [DOI: 10.1007/978-3-319-98065-2_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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