AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Abstract

Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in mitochondrial function. They are responsible for significant morbidity and mortality as they affect multiple organ systems and particularly those with high energy-utilizing tissues, such as the nervous system, skeletal muscle, and cardiac muscle. Virtually no effective treatments exist for these patients, despite the urgent need. As the majority of these conditions are monogenic and caused by mutations in nuclear genes, gene replacement is a highly attractive therapeutic strategy. Adeno-associated virus (AAV) is a well-characterized gene replacement vector, and its safety profile and ability to transduce quiescent cells nominates it as a potential gene therapy vehicle for several mitochondrial diseases. Indeed, AAV vector-based gene replacement is currently being explored in clinical trials for one mitochondrial disease (Leber hereditary optic neuropathy) and preclinical studies have been published investigating this strategy in other mitochondrial diseases. This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

“…Furthermore, efforts have been conducted in a pre-clinical stage also using AAV-mediated gene transfer for Barth syndrome; Friedreich ataxia; NDUFS4- , NDUFS3- , and SURF1 -related Leigh syndrome; ethylmalonic encephalomyopathy; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); MPV17 deficiency; TK2 deficiency; and SLC25A46-related neuropathy [ 158 ].…”

Leber hereditary optic neuropathy: new and emerging therapies

“…Gene therapy has been investigated for the treatment of various hereditary conditions, with two products so far approved by the FDA: Luxturna [an adeno-associated viral vectors (AAV)2-based product for Leber congenital amaurosis type 2 caused by mutations in the RPE65 gene] and Zolgensma (an AAV9-based product for spinal muscular atrophy type [21]. Gene therapy for LHON, based on the allotopic expression of therapeutic nuclear genes, uses AAV as a one-time curative repair of the mutated gene.…”

Amelioration of Leigh syndrome induced by mouse blastocyst complementation with a mutant human mitochondrial ATP synthase 6

“…Such alternative processing and delivery are also implicated respectively by the work of Kaeppel et al 68 and Yasuzaki et al 69 Indeed, multiple pathways to enhance DNA delivery to mitochondria in settings of gene therapy have been described and are the subjects of recent comprehensive reviews. 70,71 Early studies described entry of genetic material including naked DNA and viral particles into mitochondria and possible mechanisms of transport that included involvements of the voltage-dependent anion channel and mitochondrial permeability transition pore respectively to traverse outer and inner membranes. [21][22][23] Replication of integration deficient viral DNA, including AAV and Lentivirus in episomal configurations has also been demonstrated, [72][73][74][75][76] although the molecular pathways remain speculative.…”

“…and Yasuzaki et al 69 . Indeed, multiple pathways to enhance DNA delivery to mitochondria in settings of gene therapy have been described and are the subjects of recent comprehensive reviews 70,71 . Early studies described entry of genetic material including naked DNA and viral particles into mitochondria and possible mechanisms of transport that included involvements of the voltage‐dependent anion channel and mitochondrial permeability transition pore respectively to traverse outer and inner membranes 21–23 .…”