• ALS
• Cell therapy
• Intracerebroventricular
• Neural stem cells
• SOD1 model
• Transplantation

• Animals
• Amyotrophic Lateral Sclerosis/therapy
• Amyotrophic Lateral Sclerosis/pathology
• Amyotrophic Lateral Sclerosis/physiopathology
• Neural Stem Cells/transplantation
• Neural Stem Cells/cytology
• Humans
• Superoxide Dismutase-1/metabolism
• Mice
• Disease Models, Animal
• Mice, Transgenic
• Injections, Intraventricular
• Stem Cell Transplantation
• Treatment Outcome
• Spinal Cord/pathology

• Fondazione Revert Onlus Fondazione Revert Onlus
• 2019-ATESP-0028 Università degli Studi di Milano-Bicocca
• Dipartimenti di Eccellenza 2023-2027 to Department of Neuroscience "Rita Levi Montalcini" Ministero dell'Istruzione, dell'Università e della Ricerca
• R24-5x1000 to Fondazione IRCCS Casa Sollievo della Sofferenza Ministero della Salute
• Ministero dell’Istruzione, dell’Università e della Ricerca

• Amyotrophic lateral sclerosis
• motor neuron diseases
• personalized medicine
• stem cells
• treatment

• Amyotrophic Lateral Sclerosis/therapy
• Amyotrophic Lateral Sclerosis/genetics
• Humans
• Animals
• Stem Cell Transplantation
• Disease Models, Animal
• Clinical Trials as Topic

• Cell therapy
• Glial-restricted progenitor
• Myelin
• Oligodendrocyte
• Oligodendrocyte precursor cell
• Pre-clinical study

• 1/233209/12/NCBR/2015 "GRP&ALS" Narodowe Centrum Badań i Rozwoju
• 12/EuroNanoMed/2016 Narodowe Centrum Badań i Rozwoju
• SONATA 2017/26/D/NZ3/00721 Narodowe Centrum Nauki
• POWR.03.02.00-00-I028/17-00 European Social Fund
• SONATA 2017/26/D/NZ3/00721 the National Science Centre grant

• ALS
• astrocyte
• ephrin
• human
• motor neuron
• mouse
• neuroscience
• respiratory

• Animals
• Humans
• Mice
• Amyotrophic Lateral Sclerosis/pathology
• Astrocytes/metabolism
• Cervical Cord/metabolism
• Cervical Cord/pathology
• Diaphragm/innervation
• Disease Models, Animal
• Ephrin-B2/genetics
• Mice, Transgenic
• Neurodegenerative Diseases/pathology
• Superoxide Dismutase-1/genetics
• Superoxide Dismutase-1/metabolism

• R01 NS079702 NINDS NIH HHS
• R01 NS110385 NINDS NIH HHS
• R01NS109150 NINDS NIH HHS
• R21 NS090912 NINDS NIH HHS
• T32 GM144302 NIGMS NIH HHS
• R01 NS109150 NINDS NIH HHS
• R01NS110385 NINDS NIH HHS
• R01NS079702 NINDS NIH HHS
• RF1AG057882 NINDS NIH HHS
• R21NS090912 NINDS NIH HHS
• RF1 AG057882 NIA NIH HHS
• Muscular Dystrophy Association
• National Institute of Neurological Disorders and Stroke
• Family Strong for ALS
• Farber Family Foundation

• Amyotrophic lateral sclerosis
• Cell transplant
• Clinical trial
• Disease modeling
• Human organoid
• Oligonucleotide
• iPSC

• Amyotrophic Lateral Sclerosis/therapy
• Amyotrophic Lateral Sclerosis/genetics
• Humans
• Genetic Therapy/methods
• Animals
• Cell- and Tissue-Based Therapy/methods
• Cell- and Tissue-Based Therapy/trends
• Disease Models, Animal

• ALS
• CNS
• Cell Therapy
• GDNF
• Human iPSC
• Neurodegeneration
• Retinitis Pigmentosa
• Stem cell therapy
• iPSC

• Humans
• Rats
• Animals
• Amyotrophic Lateral Sclerosis/pathology
• Induced Pluripotent Stem Cells/pathology
• Rodentia
• Retinal Degeneration/therapy
• Retinal Degeneration/pathology
• Glial Cell Line-Derived Neurotrophic Factor/genetics
• Astrocytes/pathology
• Disease Models, Animal

• Glial cells
• Immune system
• Microglia
• Neurodegeneration
• Neurons

• Bone marrow stem cells
• Clinical trials
• Hematopoietic stem cells
• Mesenchymal stem cells
• Neural stem cells
• SOD1G93A transgenic rodents
• Umbilical cord blood stem cells

• amyotrophic lateral sclerosis
• disease mechanism
• disease model
• gain-of-toxicity
• induced pluripotent stem cell
• loss-of-support

• KU Leuven
• Agentschap voor Innovatie Door Wetenschap en Technologie
• Vlaams Instituut voor Biotechnologie
• Fonds Wetenschappelijk Onderzoek
• Target ALS
• Belgian Federal Science Policy Office
• Fondation Thierry Latran
• Association Belge Contre Les Maladies Neuro-Musculaires

• ALS
• SOD1
• amyotrophic lateral sclerosis
• astrocytes
• connexin 30
• mSOD1 mice

Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3–5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

A phase 1/2a study shows that human neural progenitor cells modified to release the growth factor GDNF are safely transplanted into the spinal cord of patients with ALS, with cell survival and GDNF production for over 3 years.

• ALS
• cellular therapy
• mesenchymal stem cell
• motor neuron degeneration
• precision medicine

• Ministry of Science and Technology, Taiwan
• Taipei Medical University

• amyotrophic lateral sclerosis
• motor neuron replacement
• neural progenitor cells
• neural stem cells
• stem cells

We analyzed the histopathological changes and the number of motor neurons (MNs) in the lumbar spinal cord of Cu/Zn superoxide dismutase transgenic (SOD1^G93ATg) mice, which are frequently used as a disease model of amyotrophic lateral sclerosis (ALS). In SOD1^G93ATg mice, hyaline inclusions and foamy vacuoles in the neuronal cell body were observed at 7 weeks of age before neurologic symptoms, and large vacuoles, spheroid formation, and nerve cell aggregation became prominent after 13 weeks of age. The number of healthy MNs was 28.7 to 37.1 cells/animal in wild-type mice and 9.3 to 13.6 cells/animal in transgenic (Tg) mice. Furthermore, the number of MNs, including degenerative neurons, in Tg mice was 27.3–36.1 cells/animal at 18 weeks of age and 17.8–19.6 cells/animal at 21 weeks of age. The present results provide useful information for the development of drugs in ALS treatment.

• astrocyte
• brain
• injury
• neurodegeneration
• spinal cord
• transplantation

• Amyotrophic lateral sclerosis
• Biomarkers
• Immunity
• Inflammation
• Target
• Targeted therapies

• Amyotrophic Lateral Sclerosis
• Animals
• Humans
• Immune System
• Neurodegenerative Diseases
• Positron-Emission Tomography

• R01 ES030049 NIEHS NIH HHS
• R01 TS000289 ATSDR CDC HHS

• astrocytes
• glial scar
• neurodegenerative disease
• neurodevelopment
• reactive astrogliosis
• therapeutic strategies

Stem cell transplantation proved promising in animal models of neurological diseases; however, in conditions with disseminated pathology such as ALS, delivery of cells and their broad distribution is challenging. To address this problem, we explored intra-arterial (IA) delivery route, of stem cells. The goal of this study was to investigate the feasibility and safety of MRI-guided transplantation of glial restricted precursors (GRPs) and mesenchymal stem cells (MSCs) in dogs suffering from ALS-like disease, degenerative myelopathy (DM). Canine GRP transplantation in dogs resulted in rather poor retention in the brain, so MSCs were used in subsequent experiments. To evaluate the safety of MSC intraarterial transplantation, naïve pigs (n = 3) were used as a pre-treatment control before transplantation in dogs. Cells were labeled with iron oxide nanoparticles. For IA transplantation a 1.2-French microcatheter was advanced into the middle cerebral artery under roadmap guidance. Then, the cells were transplanted under real-time MRI with the acquisition of dynamic T2*-weighted images. The procedure in pigs has proven to be safe and histopathology has demonstrated the successful and predictable placement of transplanted porcine MSCs. Transplantation of canine MSCs in DM dogs resulted in their accumulation in the brain. Interventional and follow-up MRI proved the procedure was feasible and safe. Analysis of gene expression after transplantation revealed a reduction of inflammatory factors, which may indicate a promising therapeutic strategy in the treatment of neurodegenerative diseases.

• Amyotrophic lateral sclerosis
• als
• clinical trials
• stem cell therapy
• stem cells

• brain pathologies
• central nervous system
• demyelinating diseases
• glial restricted precursor cells
• spinal cord injury

• Amyotrophic lateral sclerosis (ALS)
• astrocyte
• intron retention
• motor neuron
• oligomer
• protein aggregation
• reactive transformation
• splicing

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.

• A1 astrocyte
• A2 astrocyte
• TDP-43 aggregates
• amyotrophic lateral sclerosis
• astrocyte cell-based therapy
• astrocytes

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.

• Amyotrophic lateral sclerosis
• astrocytes
• excitability
• excitotoxicity
• interneurons
• lower motor neurons
• neural circuits
• upper motor neurons

• Astrocytes
• Glia
• Microglia
• Neurodegeneration
• Oligodendrocyte precursor cells
• Oligodendrocytes

• Amyotrophic lateral sclerosis
• Axonal growth
• Mesenchymal stem cells
• Neural stem cells
• Neuronal relay
• Stem cells
• Synaptic connection

• CEST MRI
• NIR imaging
• biodegradation
• gelatin
• hyaluronic acid
• hydrogel

• P41 EB024495 NIBIB NIH HHS
• R01 EB023647 NIBIB NIH HHS
• R21 EB026711 NIBIB NIH HHS
• S10 OD010744 NIH HHS

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.

• blastocyst complementation
• development
• gene editing
• organ bioengineering
• transplantation

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to understand this heterogeneity to find effective treatments. In this review, we focus on selected environmental and genetic risk factors predisposing to ALS and highlight emerging treatments in ALS therapy. Of numerous defective genes associated with ALS, we focus on four principal genes that have been identified as definite causes of ALS: the SOD1 gene, C9orf72, TDP-43, as well as the recently identified TBK1. We also provide up-to-date information on selected environmental factors that have historically been considered as key players in ALS development and pathogenesis. In parallel to our survey of known risk factors, we also discuss emerging ALS stem cell therapies and experimental medicines currently undergoing phase II and III clinical trials.

• ALS
• ALS treatment
• environmental factors
• genetic factors
• risk factors

• cytokines
• glial cell markers
• glial cells
• glial progenitors

• Behavior
• Blastocyst complementation
• Cell transplantation
• Chimera
• Cognition
• Stem cells

One of the fundamental limitations in assessing potential efficacy in Central Nervous System (CNS) transplantation of stem cells is the capacity for monitoring cell survival and migration noninvasively and longitudinally. Human glial‐restricted progenitor (hGRP) cells (Q‐Cells) have been investigated for their utility in providing neuroprotection following transplantation into models of amyotrophic lateral sclerosis (ALS) and have been granted a Food and Drug Administration (FDA) Investigational New Drug (IND) for intraspinal transplantation in ALS patients. Furthermore, clinical development of these cells for therapeutic use will rely on the ability to track the cells using noninvasive imaging methodologies as well as the verification that the transplanted GRPs have disease‐relevant activity. As a first step in development, we investigated the use of a perfluorocarbon (PFC) dual‐modal (¹⁹F magnetic resonance imaging [MRI] and fluorescence) tracer agent to label Q‐Cells in culture and following spinal cord transplantation. PFCs have a number of potential benefits that make them appealing for clinical use. They are quantitative, noninvasive, biologically inert, and highly specific. In this study, we developed optimized PFC labeling protocols for Q‐Cells and demonstrate that PFCs do not significantly alter the glial identity of Q‐Cells. We also show that PFCs do not interfere with the capacity for differentiation into astrocytes either in vitro or following transplantation into the ventral horn of the mouse spinal cord, and can be visualized in vivo by hot spot ¹⁹F MRI. These studies provide a foundation for further preclinical development of PFCs within the context of evaluating Q‐Cell transplantation in the brain and spinal cord of future ALS patients using ¹⁹F MRI. stem cells translational medicine2019;8:355–365

• 19F
• Cell tracking
• Fluorine-19
• MRI
• Perfluorocarbon
• Stem cell
• Transplantation

• Diagnosis
• Exercise
• Frontotemporal dementia
• Gene therapy
• Heterogeneity
• Nutrition
• Phenotype
• Respiratory management
• Stem cell therapy

• biomaterial
• contusion
• diaphragm
• phrenic motor neuron
• respiratory
• spinal cord injury

• Amyotrophic lateral sclerosis
• Cell therapy
• Gene therapy
• Glial cell line-derived neurotrophic factor
• Neural progenitor cells
• Stem cell transplantation

In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including SOD1-G93A mice, disassembly of the neuromuscular synapse precedes motor neuron loss and is sufficient to cause a decline in motor function that culminates in lethal respiratory paralysis. We treated SOD1-G93A mice with an agonist antibody to MuSK, a receptor tyrosine kinase essential for maintaining neuromuscular synapses, to determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The agonist antibody, delivered after disease onset, slowed muscle denervation, promoting motor neuron survival, improving motor system output, and extending the lifespan of SOD1-G93A mice. These findings suggest a novel therapeutic strategy for ALS, using an antibody format with clinical precedence, which targets a pathway essential for maintaining attachment of nerve terminals to muscle.

Amyotrophic lateral sclerosis – often shortened to ALS – is a disease that starts with difficulties moving and progresses to paralysis of many muscles, including those used for breathing. The disease is usually lethal, with patients rarely surviving more than a few years after diagnosis. There is no cure or effective treatment for the disease. It begins with the breakdown of the connections, or synapses, between the muscles and the nerve cells that connect with them. After this, the nerve cell itself breaks down. Many therapeutic approaches have focused on attempts to prevent the nerve cells from dying, but few target the initial degeneration of the synapse.

Cantor et al. asked if intervening when the synapse has already begun to break down could slow the progression of the disease in mice with ALS. Their approach involved using an antibody to bind to a receptor protein called MuSK, which plays an important role in maintaining the synapse between muscle and nerve cell. The antibody boosted the receptor’s activity, helping to preserve synapses, including those that connect nerve cells to the diaphragm muscle.

The experiments showed that the antibody treatment led to fewer synapses breaking down, and kept more of the nerve cells alive. Healthier connections between the nervous system and the diaphragm improved the function of this muscle. As a result, the mice given the antibody treatment had a slightly extended lifespan, compared with those given no treatment.

The findings suggest a possible new way to develop treatments for ALS, which could be used in combination with other therapies, such as those aimed at improving the health of the nerve cells. Together, this could improve quality of life for the majority of patients with ALS. Similar strategies could be used to develop treatments to preserve synapses in other neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease, as well as some kinds of dementia. Preserving synapses early on, before the significant loss of nerve cells, could help to slow the progression of these diseases, improve the patients' quality of life and extend their lifespans too.

• MuSK
• agonist antibody
• amyotrophic lateral sclerosis
• motor neuron
• mouse
• neurodegeneration
• neuromuscular disease
• neuroscience

• ALS
• biomarkers
• cell therapy
• clinical trials
• new drugs

• Ex vivo
• Gene therapy
• Growth factor
• Mesenchymal
• Neural
• Neurological disease
• Protection
• Stem cell

• Astrocytes
• amyotrophic lateral sclerosis
• gliosis
• motor neuron
• neurodegeneration
• oxidative stress

• Amyotrophic Lateral Sclerosis/metabolism
• Amyotrophic Lateral Sclerosis/pathology
• Amyotrophic Lateral Sclerosis/therapy
• Animals
• Astrocytes/metabolism
• Astrocytes/pathology
• Cells, Cultured
• Gliosis/diagnosis
• Gliosis/metabolism
• Gliosis/therapy
• Humans
• Motor Neurons/metabolism
• Motor Neurons/pathology
• Oxidative Stress/physiology

• R01 NS089640 NINDS NIH HHS
• R01 NS100835 NINDS NIH HHS

• Amyotrophic lateral sclerosis
• Bioluminescence imaging
• Cell survival
• Neural stem cell
• Transplantation

• Amyotrophic Lateral Sclerosis/diagnostic imaging
• Amyotrophic Lateral Sclerosis/genetics
• Amyotrophic Lateral Sclerosis/surgery
• Animals
• Cell Survival
• Disease Models, Animal
• Disease Progression
• Embryo, Mammalian
• Follow-Up Studies
• Immunosuppressive Agents/pharmacology
• Luciferases/metabolism
• Male
• Mice
• Mice, Transgenic
• Motor Activity/drug effects
• Motor Activity/physiology
• Nerve Tissue Proteins/metabolism
• Neural Stem Cells/transplantation
• Psychomotor Disorders/etiology
• Psychomotor Disorders/surgery
• Sirolimus/pharmacology
• Spinal Cord/diagnostic imaging
• Spinal Cord/surgery
• Superoxide Dismutase/genetics
• Superoxide Dismutase/metabolism
• Tacrolimus/pharmacology
• Transplantation, Homologous

• R01 NS045062 NINDS NIH HHS
• R01 NS076573 NINDS NIH HHS
• S10 OD010744 NIH HHS

No any effective treatments can prevent from the motor neuron degeneration in amyotrophic lateral sclerosis (ALS) at present. In order to modulating the endogenous neural precursor cells (NPCs) to repairing the degenerative motor neurons in ALS, we studied the alteration of endogenous vimentin-containing NPCs in olfactory bulb (OB) at the different stages of SOD1 wlid-type and G93A transgenic mice. The results showed that the vimentin-containing cells (VCCs) were mainly distributed in the glomerular layer (Gl), the accessory OB (AOB), the OB core, the granular cell layer (GRO) and the mitral cell layer (MI)+the internal plexiform layer (IPL) of the OB of adult mice. Almost all VCCs in Gl, OB core and GRO were the GFAP positive cells. Almost all VCCs in AOB were the Oligo-2 positive cells. Fewer VCCs in MI+IPL were the NeuN positive cells. VCCs significantly increased in the OB core and Gl of adult OB at the pre-onset, onset and progression stages of ALS-like G93A transgenic disease, particularly in OB core. All increased VCCs were the GFAP positive cells. Our data suggested that there extensively existed the endogenous vimentin-containing NPCs in the OB of adult mice, which was a potential resource of neural stem cells, they could differentiate into astrocyte, oligodendrocyte and neuron cells, were a potential astrocyte neuroregenerative response in adult OB in the ALS-like disease, were a potential pathway to repair the degenerated motor neurons.

• Amyotrophic lateral sclerosis
• Astrocyte cell
• Neural precursor cells
• Neural stem cells
• Olfactory bulb
• SOD1 G93A transgenic mouse.
• Vimentin

• Animals
• Animals, Newborn
• Antigens/metabolism
• Brain/pathology
• Brain Ischemia/complications
• Brain Ischemia/pathology
• Bromodeoxyuridine/metabolism
• Cell Death
• Cell Hypoxia
• Cell Proliferation
• Coculture Techniques
• Doublecortin Domain Proteins
• Female
• Glucose/deficiency
• Glutamates/metabolism
• Hippocampus/pathology
• L-Lactate Dehydrogenase
• Mice, Inbred C57BL
• Microtubule-Associated Proteins/metabolism
• Neuroglia/cytology
• Neuroglia/metabolism
• Neuropeptides/metabolism
• Neuroprotective Agents/metabolism
• Organ Culture Techniques
• Oxygen
• Pregnancy
• Proteoglycans/metabolism
• Stem Cells/cytology

• R01 NS097511 NINDS NIH HHS
• U54 HD079123 NICHD NIH HHS
• K08 NS063956 NINDS NIH HHS
• P30 HD024061 NICHD NIH HHS

• Neurologic disease
• Regeneration
• Stem cell

• Cell- and Tissue-Based Therapy/methods
• Humans
• Neurodegenerative Diseases/therapy
• Regenerative Medicine/methods
• Stem Cell Transplantation/methods

• K08 NS078555 NINDS NIH HHS
• NS078555 NINDS NIH HHS