Background: Myotonic dystrophy type 1 (DM1) is a rare, autosomal dominant, progressive neuromuscular disease caused by CTG repeat expansion (>50) in the myotonic dystrophy protein kinase (DMPK) gene. Mutant DMPK mRNA leads to sequestration of splicing factors of the muscleblind-like (MBNL) family, resulting in global splicing dysregulation in skeletal and cardiac muscle, among other tissues. AOC 1001 is an investigational therapy that delivers siRNA to muscle tissue, reducing DMPK mRNA, thereby liberating MBNL protein to correct mis-spliced events that are responsible for DM1 pathogenesis.
Method: Pharmacodynamic activity of AOC 1001 was evaluated in the phase 1/2 MARINA® study (NCT05027269) to determine target engagement and subsequent modulation of mis-splicing. RNA sequencing analysis of splicing events was performed and the intracellular concentration of functional MBNL ([MBNL]inferred) value was estimated from splicing levels (Wagner et al. 2016).
Results and Conclusions: As anticipated, DM1 participants in MARINA had spliceopathy and reduced [MBNL]inferred in muscle compared to healthy muscle. The reduced levels of [MBNL]inferred were associated with deficits in multiple functional measurements in DM1 participants. Treatment with AOC 1001 produced robust reduction of DMPK mRNA expression and a substantial dose-dependent increase in [MBNL]inferred levels in DM1 patients (2 mg/kg: 20% increase; 4 mg/kg: 34% increase), reflecting the correction of aberrant RNA splicing. More importantly, DMPK mRNA expression inversely correlated with estimated functional MBNL levels at both baseline and post-treatment timepoints, which supports the therapeutic hypothesis that AOC 1001 liberates MBNL via suppression of DMPK expression. Altogether, these data demonstrate that DMPK-reduction by AOC 1001 leads to increased estimated functional MBNL levels, which alleviates the underlying disease mechanism and results in improvement of muscle functions.
Wagner et al. PLoS Genet. 2016;12(9):e1006316