Guest Spkr Professor Thomas Voit, NIHR GOSH UCL Biomedical Research Centre, Great Ormond Street Hospital : 'Developing a gene therapy approach for Duchenne muscular dystrophy'

Gene therapy (GT) for Duchenne muscular dystrophy (DMD) is facing a number of important challenges: (i) the size of the organ skeletal muscle which makes up ~40% of the total body mass, requires large scale industrial GMP production, a challenge about to be mastered for Adeno-associated virus (AAV) as a GT shuttle; (ii) the strongly degenerative nature of the disease which poses a series of problems such as biodistribution of a transgene into fibrotic tissue, unfavourable oxidative cell environment, and progressive transgene loss; (iii) multi-organ involvement including heart and brain with different dystrophin isoforms conferring distinct functions; and (iv) the general problem of immune reaction both to the GT shuttle such as the AAV capsid and potentially against the transgene. Finally, the economic model for an expensive ‘one act’ therapy with uncertain clinical effect in the long term is not established today, and this uncertainty has dampened enthusiasm to invest heavily into this therapeutic domain in the past. Several research groups have attempted to surmount these problems, and positive results for loco-regional application or systemic application of either an exon-skipping AAV8-U7-antisense GT or a minigene-based AAV-microdystrophin therapy have been reported in the mdx mouse and in the dystrophin-deficient Golden Retriever Muscular Dystrophy (GRMD) dog model. In addition, in vitro and in vivo experiments have shown possible ways forward to counteract unfavourable tissue environment or progressive transgene loss after delivery. The next years will see the first AAV-based gene therapy trials likely using a microdystrophin approach come to the bedside. Lessons learned from the animal experiments as well as extrapolations of these GT approaches to the human will be discussed.