Background: Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene therapy, designed to compensate for absent functional dystrophin in Duchenne muscular dystrophy (DMD) by delivering a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered protein retaining key functional domains of wild-type dystrophin. Delandistrogene moxeparvovec is approved (USA, UAE, and Qatar – as of December 2023) for the treatment of ambulatory pediatric patients aged 4 through 5 years with DMD with a confirmed mutation in the DMD gene. Two cases of immune-mediated myositis (IMM) were reported in ENDEAVOR (NCT04626674), an open-label, Phase 1b, multi-cohort study of delandistrogene moxeparvovec (deletion of exons 3–43 [Case 1] and 8–9 [Case 2] of the DMD gene). These two patients experienced muscle weakness and received immunosuppressive treatment, including high-dose steroids and tacrolimus.
Objective: To investigate antigenic features mediating IMM in these two patients.
Methods: An IFN-γ ELISpot assay was used to detect T-cell responses to delandistrogene moxeparvovec micro-dystrophin peptide pools. An in silico tool was used to determine micro-dystrophin peptide binding with HLA-I or HLA-II molecules corresponding to the patients’ specific HLA allele combinations.
Results: ELISpot analysis suggested that IMM resulted from T cell-mediated responses directed against specific delandistrogene moxeparvovec micro-dystrophin peptides corresponding to exons 8 and 9 (Case 1) and exon 8 (Case 2) of the DMD gene. In silico analysis of HLA presentation suggested a high risk of immunogenicity for peptides derived from exons 8 and 9 of the DMD gene.
Conclusions: These results are consistent with clinical trials of other investigational DMD gene therapies suggesting that patients with deletions in regions of the DMD gene overlapping those expressed in a given micro‑dystrophin may be at an increased risk of IMM following gene therapy. Future work may provide a better understanding of risk factors to mitigate safety concerns in patients with potentially higher-risk DMD mutations.