G.P.104: Oral small molecule compounds that promote the skipping of exon 51 in the DMD gene

Abstract

Duchenne muscular dystrophy (DMD) is a severe progressive X-linked genetic disorder that affects 1 in 3500 males. It is a monogenic disease caused by mutations in the gene encoding the dystrophin protein. Approximately two thirds of the mutations are deletions in the open reading frame that result in the production of C-terminus-truncated non-functional dystrophin protein. One potential therapeutic approach to address a subset of the reading frame-altering deletions, located in the central rod domain, is to cause skipping of an exon downstream of the deletion thereby restoring the reading frame. The resulting protein, containing an internal deletion, would be partially functional but expected to lead to a milder, Becker muscular dystrophy-like phenotype. The largest fraction (∼13%) of all DMD patients have the above described mutations that can be addressed by skipping exon 51. We are pursuing an innovative approach to discover and develop orally bioavailable tissue-penetrable small molecules that induce skipping of DMD exon 51. Using PTC’s proprietary drug discovery platform technology referred to as GEMS AS (Gene Expression Modulation by Small-molecules – Alternative Splicing™) we have designed and conducted a high throughput screen of our compound library. We identified several structurally distinct classes of small molecules that promote the skipping of DMD exon 51. These scaffolds are undergoing structural optimization to improve biological, pharmacological and pharmaceutical properties with the ultimate goal of identifying a Drug Candidate for preclinical and clinical development.