Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. DM1 is caused by an expanded CTG repeat in the 3′- untranslated region of DMPK, the gene encoding Dystrophia Myotonica-Protein Kinase. Antisense oligonucleotides (ASOs) containing constrained ethyl-modified (cEt) residues exhibit significant RNA binding affinity. The present study describes the characterization of a cEt gapmer DMPK ASO (ISIS 486178) with potent activity against mouse, monkey and human DMPK. Delivery of ISIS 486718 to human DMPK transgenic mice or cynomolgus monkeys with led to 70% inhibition of DMPK in multiple skeletal muscles and ∼50% in cardiac muscle. Importantly, inhibition of DMPK was well tolerated and the inhibition of DMPK mRNA levels in muscle was maintained for 13 to 16 weeks. These results suggest that this approach warrants further clinical investigation to inhibit the gain-of-function toxic RNA underlying the pathogenesis of DM1.
See article at J Pharmacol Exp Ther 2015, 355:329-340.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics