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Park SH. Potential of ginsenoside Rg1 to treat aplastic anemia via mitogen activated protein kinase pathway in cyclophosphamide-induced myelosuppression mouse model. World J Stem Cells 2024; 16:900-905. [DOI: 10.4252/wjsc.v16.i11.900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/12/2024] [Accepted: 11/20/2024] [Indexed: 11/26/2024] Open
Abstract
Aplastic anemia (AA) is a rare but serious condition in which the bone marrow fails to produce sufficient new blood cells, leading to fatigue, increased susceptibility to infection, and uncontrolled bleeding. In this editorial, we review and comment on an article by Wang et al published in 2024. This study aimed to evaluate the potential therapeutic benefits of ginsenoside Rg1 in AA, focusing on its protective effects and uncovering the underlying mechanisms. Cyclophosphamide (CTX) administration caused substantial damage to the structural integrity of the bone marrow and decreased the number of hematopoietic stem cells, thereby establishing an AA model. Compared with the AA group, ginsenoside Rg1 alleviated the effects of CTX by reducing apoptosis and inflammatory factors. Mechanistically, treatment with ginsenoside Rg1 significantly mitigated myelosuppression in mice by inhibiting the mitogen activated protein kinase signaling pathway. Thus, this study indicates that ginsenoside Rg1 could be effective in treating AA by reducing myelosuppression, primarily through its influence on the mitogen activated protein kinase signaling pathway. We expect that our review and comments will provide valuable insights for the scientific community related to this research and enhance the overall clarity of this article.
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Affiliation(s)
- See-Hyoung Park
- Biological and Chemical Engineering, Hongik University, Sejong 30016, South Korea
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2
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Hughes AD, Kurre P. The impact of clonal diversity and mosaicism on haematopoietic function in Fanconi anaemia. Br J Haematol 2021; 196:274-287. [PMID: 34258754 DOI: 10.1111/bjh.17653] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/28/2021] [Indexed: 12/17/2022]
Abstract
Recent advances have facilitated studies of the clonal architecture of the aging haematopoietic system, and provided clues to the mechanisms underlying the origins of hematopoietic malignancy. Much less is known about the clonal composition of haematopoiesis and its impact in bone marrow failure (BMF) disorders, including Fanconi anaemia (FA). Understanding clonality in FA is likely to inform both the marked predisposition to cancer and the rapid erosion of regenerative reserve seen with this disease. This may also hold broader lessons for haematopoietic stem cell biology in other diseases with a clonal restriction. In this review, we focus on the conceptual basis and available tools to study clonality, and highlight insights in somatic mosaicism and malignant evolution in FA in the context of haematopoietic failure and gene therapy.
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Affiliation(s)
- Andrew D Hughes
- Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Peter Kurre
- Comprehensive Bone Marrow Failure Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.,Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
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Srikanthan MA, Humbert O, Haworth KG, Ironside C, Rajawat YS, Blazar BR, Palchaudhuri R, Boitano AE, Cooke MP, Scadden DT, Kiem HP. Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 17:455-464. [PMID: 32226796 PMCID: PMC7096734 DOI: 10.1016/j.omtm.2020.02.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/03/2020] [Indexed: 02/08/2023]
Abstract
Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient’s marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.
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Affiliation(s)
- Meera A Srikanthan
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Seattle Children's Hospital, Seattle, WA, USA
| | - Olivier Humbert
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Kevin G Haworth
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Christina Ironside
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Yogendra S Rajawat
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA
| | | | | | | | - David T Scadden
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Hans-Peter Kiem
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA.,Department of Pathology, University of Washington, Seattle, WA, USA
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Radtke S, Humbert O, Kiem HP. Mouse models in hematopoietic stem cell gene therapy and genome editing. Biochem Pharmacol 2019; 174:113692. [PMID: 31705854 DOI: 10.1016/j.bcp.2019.113692] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 11/01/2019] [Indexed: 12/26/2022]
Abstract
Gene therapy has become an important treatment option for a variety of hematological diseases. The biggest advances have been made with CAR T cells and many of those studies are now FDA approved as a routine treatment for some hematologic malignancies. Hematopoietic stem cell (HSC) gene therapy is not far behind with treatment approvals granted for beta-hemoglobinopathies and adenosine deaminase severe combined immune deficiency (ADA-SCID), and additional approbations currently being sought. With the current pace of research, the significant investment of biotech companies, and the continuously growing toolbox of viral as well as non-viral gene delivery methods, the development of new ex vivo and in vivo gene therapy approaches is at an all-time high. Research in the field of gene therapy has been ongoing for more than 4 decades with big success stories as well as devastating drawbacks along the way. In particular, the damaging effect of uncontrolled viral vector integration observed in the initial gene therapy applications in the 90s led to a more comprehensive upfront safety assessment of treatment strategies. Since the late 90s, an important read-out to comprehensively assess the quality and safety of cell products has come forward with the mouse xenograft model. Here, we review the use of mouse models across the different stages of basic, pre-clinical and translational research towards the clinical application of HSC-mediated gene therapy and editing approaches.
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Affiliation(s)
- Stefan Radtke
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Olivier Humbert
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
| | - Hans-Peter Kiem
- Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
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5
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Abstract
Fanconi anemia (FA) is a rare inherited disease that is associated with bone marrow failure and a predisposition to cancer. Previous clinical trials emphasized the difficulties that accompany the use of gene therapy to treat bone marrow failure in patients with FA. Nevertheless, the discovery of new drugs that can efficiently mobilize hematopoietic stem cells (HSCs) and the development of optimized procedures for transducing HSCs, using safe, integrative vectors, markedly improved the efficiency by which the phenotype of hematopoietic repopulating cells from patients with FA can be corrected. In addition, these achievements allowed the demonstration of the in vivo proliferation advantage of gene-corrected FA repopulating cells in immunodeficient mice. Significantly, new gene therapy trials are currently ongoing to investigate the progressive restoration of hematopoiesis in patients with FA by gene-corrected autologous HSCs. Further experimental studies are focused on the ex vivo transduction of unpurified FA HSCs, using new pseudotyped vectors that have HSC tropism. Because of the resistance of some of these vectors to serum complement, new strategies for in vivo gene therapy for FA HSCs are in development. Finally, because of the rapid advancements in gene-editing techniques, correction of CD34+ cells isolated from patients with FA is now feasible, using gene-targeting strategies. Taken together, these advances indicate that gene therapy can soon be used as an efficient and safe alternative for the hematopoietic treatment of patients with FA.
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Affiliation(s)
- Paula Río
- 1 Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain; Madrid, Spain .,2 Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain; and Madrid, Spain .,3 Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD) , Madrid, Spain
| | - Susana Navarro
- 1 Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain; Madrid, Spain .,2 Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain; and Madrid, Spain .,3 Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD) , Madrid, Spain
| | - Juan A Bueren
- 1 Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain; Madrid, Spain .,2 Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain; and Madrid, Spain .,3 Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD) , Madrid, Spain
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Haworth KG, Ironside C, Ramirez MA, Weitz S, Beard BC, Schwartz JD, Adair JE, Kiem HP. Minimal conditioning in Fanconi anemia promotes multi-lineage marrow engraftment at 10-fold lower cell doses. J Gene Med 2018; 20:e3050. [PMID: 30129972 DOI: 10.1002/jgm.3050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/10/2018] [Accepted: 08/11/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Gene therapy approaches for the treatment of Fanconi anemia (FA) hold promise for patients without a suitably matched donor for an allogeneic bone marrow transplant. However, significant limitations include the collection of sufficient stem cell numbers from patients, the fragility of these cells during ex vivo manipulation, and clinically meaningful engraftment following transplantation. With these challenges in mind, we were interested in determining (i) whether gene-corrected cells at progressively lower numbers can successfully engraft in FA; (ii) whether low-dose conditioning facilitates this engraftment; and (iii) whether these cells can be selected for post-transplant. METHODS Utilizing a well characterized mouse model of FA, we infused donor bone marrow from healthy heterozygote littermates that are unaffected carriers of the FANCA mutation to mimic a gene-corrected product, after administering low-dose conditioning. Once baseline engraftment was observed, we administered a second, very-low selective dose to determine whether gene-corrected cells could be selected for in vivo. RESULTS We demonstrate that upfront low-dose conditioning greatly increases successful engraftment of hematopoietic corrected cells in a pre-clinical animal model of FA. Additionally, without conditioning, cells can still engraft and demonstrate a selective advantage in vivo over time following transplantation, and these corrected cells can be directly selected for in vivo after engraftment. CONCLUSIONS Minimal conditioning prior to bone marrow transplant in Fanconi anemia promotes the multi-lineage engraftment of 10-fold fewer cells compared to nonconditioned controls. These data provide important insights into the potential of minimally toxic conditioning protocols for FA gene therapy applications.
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Affiliation(s)
- Kevin G Haworth
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Christina Ironside
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Megan A Ramirez
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Sarah Weitz
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | | | - Jennifer E Adair
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
| | - Hans-Peter Kiem
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA.,Department of Pathology, University of Washington, Seattle, WA, USA
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