In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency.

ABSTRACT: Friedreich's ataxia is a rare disorder resulting from deficiency of frataxin, a mitochondrial protein implicated in the synthesis of iron-sulfur clusters. Preclinical studies in mice have shown that gene therapy is a promising approach to treat individuals with Friedreich's ataxia. However, a recent report provided evidence that AAVrh10-mediated overexpression of frataxin could lead to cardiotoxicity associated with mitochondrial dysfunction. While evaluating an AAV9-based frataxin gene therapy using a chicken β-actin promoter, we showed that toxic overexpression of frataxin could be reached in mouse liver and heart with doses between 1 × 10¹³ and 1 × 10¹⁴ vg/kg. In a mouse model of cardiac disease, these doses only corrected cardiac dysfunction partially and transien

SUBMITTER: Huichalaf C 

PROVIDER: S-EPMC8866050 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature