Gene therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies.

Abstract

Mitochondrial disorders are a clinically heterogeneous group of diseases due to defects in nuclear or mitochondrial DNA-encoded genes leading to mitochondrial dysfunction and oxidative phosphorylation deficiency in the affected tissues. The dual genetic controls, the biochemical heterogeneity, and the clinical variability challenge the development of effective treatment. In this review, we will focus on gene therapy and mRNA drug approaches for nuclear-encoded gene defects causing isolated, combined, or multiple oxidative phosphorylation defects and mitochondrial-encoded gene defects for which a gene replacement approach has been tested, and on the allotopic expression of mtDNA genes. An overview of the available in vitro and in vivo disease models and pre-clinical data of safety and efficacy is provided and highlights challenges in correcting the biochemical defect in the most affected tissues. Future perspectives with the use of novel gene-editing approaches or gene replacement delivery with nanoparticles are also considered as a novel strategy for treating mitochondrial disorders.