Gene therapy for mitochondrial disorders

Abstract

In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno‐associated virus‐based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator‐like effector nucleases, zinc‐finger nucleases, and meganucleases (mitoARCUS). rAAV‐based approaches have been used successfully to deliver these nucleases in vivo in mice. Exciting developments in CRISPR‐Cas9 gene editing technology have achieved in vivo gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR‐free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.

Mission possible: Gene therapy for inherited metabolic diseases

“…15 Keshavan et al provide a perspective on the development of gene therapy for primary mitochondrial diseases. 16 Ng et al show the epic journey to develop gene therapy approaches for inherited neurotransmitter defects culminating with the recent approval of eladocagene exuparvovec (Upstaza™) for aromatic L-amino acid decarboxylase (AADC) deficiency in late 2022. 17 To conclude this special issue, Waddington et al present a magistral review of fetal gene therapy and its complex implications from preclinical evidence to translation, safety and ethics for both the fetus and the mother.…”