Duchenne Muscular Dystrophy (DMD) is a debilitating disease caused by the absence of dystrophin, a protein expressed in muscle fibers. This X-linked disease affects 1 in 3000/4000 male births and average life expectancy is 26. While improvements in cardiac and respiratory care have led to significant extensions in life expectancy, there are limited options for targeting the root cause of the disease, namely the absence of dystrophin protein.
Since shorter forms of dystrophin can partially reinstate muscle function, a number of promising approaches revolve around attaining this goal, namely restoring expression of smaller versions of dystrophin. Amongst these, approaches that bypass expression of pathogenic exons, such as exon-skipping and microdystrophin gene therapy are the most promising.
Gene editing can also be used to obtain specific and permanent exon-skipping. Using a CRISPR-Cas9 system, the Wagers lab has designed and developed therapeutic gRNAs that circumvent expression of undesirable exons (exon 23 or exons 52/53) and allow expression of truncated dystrophin. These genetic changes are permanent and thus represent a distinct advantage over other modalities that require repeat administrations-- like gene therapy or oligonucleotide-based exon skipping. Most importantly, these results were achieved (i) in vivo (ii) upon systemic administration and (iii) lead to functional improvements in muscle function. A similar strategy can be applied to other therapeutic areas where exon skipping can result in disease amelioration (SMA, CCR5 deletion in HIV etc.,.)