P.20.15 Assessing T cell-mediated immune response to dystrophin in the natural history of Duchenne muscular dystrophy

Abstract

The pre-symptomatic induction of inflammatory cascades and invasion of muscle by immune cells in dystrophin deficient muscle contributes to the pathology of Duchenne muscular dystrophy (DMD). Traditional and RNA-based gene therapy approaches for DMD are progressing through clinical development. Whilst in one study a post-treatment reduction in inflammatory infiltrate after antisense oligonucleotide-mediated exon skipping has been reported; another study, on viral delivered mini-dystrophin, has shown evidence that dystrophin epitopes expressed in revertant fibres can elicit T cell production in untreated patients which may accelerate a post-treatment immune response. To extend this observation, we are performing annual ELISPOT IFN-gamma assays on patients recruited into a four year DMD natural history study. The study is recruiting 30 ambulant and 30 non-ambulant DMD boys with exon skippable deletions from three clinical centres. ELISPOT assays on all patients are performed with a full length dystrophin peptide set whilst patients with exon 51 or 53 skippable deletions are also assessed with peptides corresponding to unique epitopes generated by exon skipping. This allows us to assess pre-existing immunological responses to dystrophin epitopes in patients prior to inclusion in clinical trials, as well as the likelihood of a post-exon skipping immune response to newly-generated dystrophin protein. Here we present the results to date from patients recruited during the first year; we correlated data to factors such as age, ambulation status, steroid regime and DMD deletion. The majority of patients did not have significant T cell activity against the full length or unique epitope peptide sets; whilst in those that did (approximately 1/6), the activity was relatively low. These ’positive’ patients are presented and the responses mapped to specific dystrophin peptides. Our data provides a useful immunological baseline for future DMD clinical trials.