AAV8 Gene Therapy Reverses Cardiac Pathology and Prevents Early Mortality in a Mouse Model of Friedreich’s Ataxia

Abstract

Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein, frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of FRDA’s cardiac phenotype was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxn^flox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has a FXN gene ablation that prevents frataxin expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN gene under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks post dose. Frataxin protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild-type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.