TY - JOUR
T1 - Immunologic investigations into transgene directed immune-mediated myositis following delandistrogene moxeparvovec gene therapy
AU - Potter, Rachael A.
AU - Moeller, Ida H.
AU - Khan, Sohrab
AU - Haegel, Hélène
AU - Hollenstein, Andreas
AU - Steiner, Guido
AU - Wandel, Christoph
AU - Murphy, Alexander P.
AU - Asher, Damon R.
AU - Palatinsky, Emanuel
AU - Griffin, Danielle A.
AU - Mason, Stefanie
AU - Iannaccone, Susan T.
AU - Zaidman, Craig M.
AU - Rodino-Klapac, Louise R.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
KW - AAV vector
KW - Delandistrogene moxeparvovec
KW - Duchenne muscular dystrophy
KW - Dystrophin
KW - Gene transfer therapy
KW - Immune-mediated myositis
UR - http://www.scopus.com/inward/record.url?scp=85214033570&partnerID=8YFLogxK
U2 - 10.1038/s41598-024-84077-w
DO - 10.1038/s41598-024-84077-w
M3 - Article
C2 - 39747998
AN - SCOPUS:85214033570
SN - 2045-2322
VL - 15
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 4
ER -