AAV-TNNI3 rescues an experimental murine Tnni3 mutation resulting in thin filament mediated DCM.

Cardiac thin filament mutations in TNNI3 are associated with up to 3 % of hypertrophic (HCM) cardiomyopathy cases and contribute to severe restrictive (RCM) and dilated (DCM) cardiomyopathy caseloads. As such, thin filament cardiomyopathy mediated by TNNI3 mutations is an orphan disease with unmet therapeutic need. Gene therapy is one approach to addressing orphan disease but has been restricted to the repletion of protein deficiency. Based on the best available knowledge, TNNI3 gene therapy has never been applied in the context of a functional mutant protein. Described here is the viral gene therapy rescue at a 4-month endpoint of an experimental murine Tnni3 mutation resulting in slow-onset dilated cardiomyopathy (DCM) with cardiac failure at 12-18 months. Mutant mice treated with AAV encoding wild-type (WT) human TNNI3 at 1.0E+14 vg/kG prevented the onset of DCM pathology. This work describes the first adeno-associated virus (AAV) gene therapy replacement of functional mutated Tnni3 protein. The results suggest a broader application of gene therapy for gene replacement.