Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy
Abstract Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in DMD. It is approved in the US and i...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-024-84077-w |
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| author | Rachael A. Potter Ida H. Moeller Sohrab Khan Hélène Haegel Andreas Hollenstein Guido Steiner Christoph Wandel Alexander P. Murphy Damon R. Asher Emanuel Palatinsky Danielle A. Griffin Stefanie Mason Susan T. Iannaccone Craig M. Zaidman Louise R. Rodino-Klapac |
| author_facet | Rachael A. Potter Ida H. Moeller Sohrab Khan Hélène Haegel Andreas Hollenstein Guido Steiner Christoph Wandel Alexander P. Murphy Damon R. Asher Emanuel Palatinsky Danielle A. Griffin Stefanie Mason Susan T. Iannaccone Craig M. Zaidman Louise R. Rodino-Klapac |
| author_sort | Rachael A. Potter |
| collection | DOAJ |
| description | Abstract Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in DMD. It is approved in the US and in other select countries. Two serious adverse event cases of immune-mediated myositis (IMM) were reported in the phase Ib ENDEAVOR trial (NCT04626674). We hypothesized that immune responses to the micro-dystrophin transgene product may have mediated these IMM events. An interferon-gamma ELISpot assay was used to detect T cell responses to delandistrogene moxeparvovec micro-dystrophin peptide pools. ELISpot analysis suggested that IMM resulted from T cell-mediated responses directed against specific micro-dystrophin peptides corresponding to exons 8 and 9 (Case 1) and exon 8 (Case 2) of the DMD gene. In silico epitope mapping based on the patients’ HLA-I alleles indicated greater probability for peptides derived from exons 8 and/or 9 to bind HLA-I, providing further evidence that peptides derived from corresponding micro-dystrophin regions may have higher immunogenic potential. Collectively, these data suggest that patients with DMD gene deletions involving exons 8 and/or 9 may be at increased risk of IMM following delandistrogene moxeparvovec micro-dystrophin gene therapy infusion. |
| format | Article |
| id | doaj-art-b648a6f0cd604c748bdf4b7ade3a3ca1 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-b648a6f0cd604c748bdf4b7ade3a3ca12025-01-05T12:15:58ZengNature PortfolioScientific Reports2045-23222025-01-0115111110.1038/s41598-024-84077-wImmunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapyRachael A. Potter0Ida H. Moeller1Sohrab Khan2Hélène Haegel3Andreas Hollenstein4Guido Steiner5Christoph Wandel6Alexander P. Murphy7Damon R. Asher8Emanuel Palatinsky9Danielle A. Griffin10Stefanie Mason11Susan T. Iannaccone12Craig M. Zaidman13Louise R. Rodino-Klapac14Sarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.F. Hoffmann-La Roche LtdF. Hoffmann-La Roche LtdF. Hoffmann-La Roche LtdF. Hoffmann-La Roche LtdRoche Products LtdSarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center and Children’s HealthDepartment of Neurology, Washington University in St. LouisSarepta Therapeutics, Inc.Abstract Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in DMD. It is approved in the US and in other select countries. Two serious adverse event cases of immune-mediated myositis (IMM) were reported in the phase Ib ENDEAVOR trial (NCT04626674). We hypothesized that immune responses to the micro-dystrophin transgene product may have mediated these IMM events. An interferon-gamma ELISpot assay was used to detect T cell responses to delandistrogene moxeparvovec micro-dystrophin peptide pools. ELISpot analysis suggested that IMM resulted from T cell-mediated responses directed against specific micro-dystrophin peptides corresponding to exons 8 and 9 (Case 1) and exon 8 (Case 2) of the DMD gene. In silico epitope mapping based on the patients’ HLA-I alleles indicated greater probability for peptides derived from exons 8 and/or 9 to bind HLA-I, providing further evidence that peptides derived from corresponding micro-dystrophin regions may have higher immunogenic potential. Collectively, these data suggest that patients with DMD gene deletions involving exons 8 and/or 9 may be at increased risk of IMM following delandistrogene moxeparvovec micro-dystrophin gene therapy infusion.https://doi.org/10.1038/s41598-024-84077-wAAV vectorDelandistrogene moxeparvovecDuchenne muscular dystrophyDystrophinGene transfer therapyImmune-mediated myositis |
| spellingShingle | Rachael A. Potter Ida H. Moeller Sohrab Khan Hélène Haegel Andreas Hollenstein Guido Steiner Christoph Wandel Alexander P. Murphy Damon R. Asher Emanuel Palatinsky Danielle A. Griffin Stefanie Mason Susan T. Iannaccone Craig M. Zaidman Louise R. Rodino-Klapac Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy Scientific Reports AAV vector Delandistrogene moxeparvovec Duchenne muscular dystrophy Dystrophin Gene transfer therapy Immune-mediated myositis |
| title | Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy |
| title_full | Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy |
| title_fullStr | Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy |
| title_full_unstemmed | Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy |
| title_short | Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy |
| title_sort | immunologic investigations into transgene directed immune mediated myositis following delandistrogene moxeparvovec gene therapy |
| topic | AAV vector Delandistrogene moxeparvovec Duchenne muscular dystrophy Dystrophin Gene transfer therapy Immune-mediated myositis |
| url | https://doi.org/10.1038/s41598-024-84077-w |
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