T Cell Responses to Dystrophin in a Natural History Study of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, but many patients have rare revertant fibers that express dystrophin. The skeletal muscle pathology of DMD patients includes immune cell infiltration and inflammatory cascades. There are several strategies to restore dystrophin in skeletal muscles of patients, including exon skipping and gene therapy. There is some evidence that dystrophin restoration leads to a reduction in immune cells, but dystrophin epitopes expressed in revertant fibers or following genome editing, cell therapy, or microdystrophin delivery after adeno-associated viral gene therapy may elicit T cell production in patients. This may affect the efficacy of the therapeutic intervention, and potentially lead to serious adverse events. To confirm and extend previous studies, we performed annual enzyme- linked immunospot interferon-gamma assays on peripheral blood mononuclear cells from 77 pediatric boys with DMD recruited into a natural history study, 69 of whom (89.6%) were treated with corticosteroids. T cell responses to dystrophin were quantified using a total of 368 peptides spanning the entire dystrophin protein, organized into nine peptide pools. Peptide mapping pools were used to further localize the immune response in one positive patient. Six (7.8%) patients had a T cell-mediated immune response to dystrophin at at least one time point. All patients who had a positive result had been treated with corticosteroids, either prednisolone or prednisone. Our results show that similar to 8% of DMD individuals in our cohort have a pre-existing T cell-mediated immune response to dystrophin, despite steroid treatment. Although these responses are relatively low level, this information should be considered a useful immunological baseline before undertaking clinical trials and future DMD studies. We further highlight the importance for a robust, reproducible standard operating procedure for collecting, storing, and shipping samples from multiple centers to minimize the number of inconclusive data.

Automated summary

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the lack of dystrophin protein. Some patients with DMD have rare fibers that express dystrophin. The muscle pathology of DMD includes inflammation and immune cell infiltration. Strategies to restore dystrophin expression in DMD patients include exon skipping and gene therapy. However, restoring dystrophin may trigger T cell-mediated immune responses in patients, which can affect treatment efficacy and lead to adverse events. A study on pediatric boys with DMD found that approximately 8% of patients had pre-existing T cell-mediated immune responses to dystrophin, despite steroid treatment. This information is important for considering immunological baseline before clinical trials and future studies on DMD.