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Clinical Trial
. 2025 Jan 2;15(1):4.
doi: 10.1038/s41598-024-84077-w.

Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy

Rachael A Potter  1 , Ida H Moeller  1 , Sohrab Khan  1 , Hélène Haegel  2 , Andreas Hollenstein  2 , Guido Steiner  2 , Christoph Wandel  2 , Alexander P Murphy  3 , Damon R Asher  1 , Emanuel Palatinsky  1 , Danielle A Griffin  1 , Stefanie Mason  1 , Susan T Iannaccone  4 , Craig M Zaidman  5 , Louise R Rodino-Klapac  6
Affiliations
Clinical Trial

Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy

Rachael A Potter et al. Sci Rep. .

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.

Keywords: AAV vector; Delandistrogene moxeparvovec; Duchenne muscular dystrophy; Dystrophin; Gene transfer therapy; Immune-mediated myositis.

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Conflict of interest statement

Declarations. Competing interests: R.A.P., I.H.M., S.K., D.R.A., E.P., D.A.G., and S.M. are employees of Sarepta Therapeutics and may have stock options. H.H., A.H., G.S., and C.W. are employees of F. Hoffmann-La Roche Ltd and may have stock options. A.P.M. is an employee of Roche Products Ltd and may have stock options. S.T.I. receives research support from industry (Elpida, Novartis, Biogen, Sarepta Therapeutics, PTC Therapeutics, Scholar Rock, FibroGen, RegenxBio, and ReveraGen) and the Department of Defense W81XWH2010293, Parent Project Muscular Dystrophy, and Cure SMA. She has served on medical advisory boards for Novartis, Biogen, Genentech, and Sarepta Therapeutics. She receives partial salary support from the following grants: National Institutes of Health Wellstone Muscular Dystrophy Center P50HD087351, NeuroNEXT U24NS107176, and the Muscular Dystrophy Association. C.M.Z. receives research support from Biogen and Novartis and has served on an advisory board for Sarepta Therapeutics. L.R.R.K. is an employee of Sarepta Therapeutics and may have stock options and is a co-inventor of AAVrh74.MHCK7.SRP-9001-dys technology.

Figures

Fig. 1
Fig. 1
Outcome of the IMM cases. (A) Outcome of IMM Case 1, (B) Outcome of IMM Case 2. *Steroids were administered as part of gene therapy treatment. BID twice daily, BiPAP bilevel positive airway pressure, BNP brain natriuretic peptide, BUN blood urea nitrogen, CK creatine kinase, cMRI cardiac magnetic resonance imaging, CXR chest X-ray, ECG electrocardiogram, ECHO echocardiogram, EDVi end-diastolic volume, ELISpot enzyme-linked immunosorbent spot, ESR erythrocyte sedimentation rate, Hct hematocrit, Hg hemoglobin, IMM immune-mediated myositis, INR international normalized ratio, IVIG intravenous immunoglobulin, LFT liver function test, MRI magnetic resonance imaging, NG nasogastric tube, NSAA North Star Ambulatory Assessment, PTT partial thromboplastin time, Strep Streptococcus pyogenes, WBC white blood cell.
Fig. 2
Fig. 2
ELISpot assay pools. (A) Overview of the full-length dystrophin domains and exons alongside delandistrogene moxeparvovec micro-dystrophin. Combinations of peptides from regions of delandistrogene moxeparvovec micro-dystrophin were selected to form the MDys peptide pools—MDys pools 1, 2, and 3—used for the IFN-γ ELISpot assay, (B) Genomic deletions of the two patients who had an IMM event. Adapted from Iannaccone ST, et al. J Neurol. 2024;271(8):5659–5664. Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). ABD actin binding domain, CR cysteine-rich domain, cont. continued, CT C-terminal domain, ELISpot enzyme-linked immunosorbent spot, H hinge domain, IFN-γ interferon-gamma, MDys micro-dystrophin, R spectrin‑like repeat domain.
Fig. 3
Fig. 3
Cellular immune response to micro-dystrophin. (A) IMM Case 1, (B) IMM Case 2. BL baseline, D day, IFN-γ interferon-gamma, IMM immune-mediated myositis, MDys micro-dystrophin, PBMC peripheral blood mononuclear cell, SFC spot-forming cell, W week.
Fig. 4
Fig. 4
ELISpot analysis of micro-dystrophin peptide pool MDys1 to identify potential T cell targets. (A): IMM Case 1, (B): IMM Case 2. *MDys pool, peptide numbers, and IFN-γ response omitted for brevity. ABD actin binding domain, ELISpot enzyme-linked immunosorbent spot, H hinge domain, IFN-γ interferon-gamma, IMM immune-mediated myositis, MDys micro-dystrophin, N N-terminal domain, PHA phytohemagglutinin, SD standard deviation.
Fig. 5
Fig. 5
In silico HLA-I epitope mapping and scoring. (A) IMM Case 1, (B) IMM Case 2. The sums of transformed scores (epitope scores) are shown for the protein sequences derived from each exon 1 to 17. HLA human leukocyte antigen, IMM immune-mediated myositis.
Fig. 6
Fig. 6
Summary of ELISpot and in silico HLA-epitope mapping findings. ELISpot enzyme-linked immunosorbent spot, HLA human leukocyte antigen, IMM immune-mediated myositis, MHC major histocompatibility complex, TCR T cell receptor.
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