Progress and prospects: gene therapy for mitochondrial DNA disease

Kyriakouli, D S; Boesch, Pierre; Taylor, Robert W.; Lightowlers, Robert N.

doi:10.1038/gt.2008.91

Cited by 72 publications

(51 citation statements)

References 21 publications

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“…Liposomebased carriers can import hybrid molecules into mitochondria of whole cells, but this approach suffers from low efficiency and high cytotoxicity (8,25,39). Mutated mtDNA can be removed from the germ line by transfer of the spindle-chromosomal complex from one egg to another that is enucleated and depleted of its mitochondria (40).…”

Section: Discussionmentioning

confidence: 99%

“…Others can appear from mutations in nuclear genes that are required for mtDNA replication, oxidative phosphorylation (OXPHOS), and structure of the organelle (1,5,6). There is currently no effective remedy for any of these disorders, especially for those caused by mutations in the mitochondrial genome (5,(7)(8)(9). To date, more than 200 pathogenic mtDNA mutations have been identified that are associated with a large spectrum of clinical phenotypes, many of which are fatal (10,11).…”

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confidence: 99%

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Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model

Koilkonda

Chou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

169

163

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To introduce DNA into mitochondria efficiently, we fused adenoassociated virus capsid VP2 with a mitochondrial targeting sequence to carry the mitochondrial gene encoding the human NADH ubiquinone oxidoreductase subunit 4 ( ND4 ). Expression of WT ND4 in cells with the G11778A mutation in ND4 led to restoration of defective ATP synthesis. Furthermore, with injection into the rodent eye, human ND4 DNA levels in mitochondria reached 80% of its mouse homolog. The construct expressed in most inner retinal neurons, and it also suppressed visual loss and optic atrophy induced by a mutant ND4 homolog. The adenoassociated virus cassette accommodates genes of up to ∼5 kb in length, thus providing a platform for introduction of almost any mitochondrial gene and perhaps even allowing insertion of DNA encompassing large deletions of mtDNA, some associated with aging, into the organelle of adults.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model

Koilkonda

Chou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

169

163

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“…Despite a significant need, there are currently no effective treatments for deleterious mtDNA alterations. DNA import into mitochondria to repair mtDNA alterations has been difficult and low in efficiency, so approaches at mitochondrial repair have exploited import pathway mechanisms (24). For example, allotopic expression of a subset of mitochondrial genes (recoded mtDNA expressed from the nucleus) has been explored to partially correct the effects of deleterious mutations for some mitochondrial genes, including tRNAs (25)(26)(27).…”

mentioning

confidence: 99%

Correcting human mitochondrial mutations with targeted RNA import

Wang¹,

Shimada²,

Zhang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

120

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Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects, and aging. An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA (mtDNA) alterations has unfortunately remained elusive. Here, we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA, the RNA component of the human RNase P enzyme, appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria. The methodology is effective for both noncoding RNAs, such as tRNAs, and mRNAs. The RNA import component, polynucleotide phosphorylase (PNPASE), facilitates transfer of this hybrid RNA into the mitochondrial matrix. In addition, nucleus-encoded mRNAs for mitochondrial proteins, such as the mRNA of human mitochondrial ribosomal protein S12 (MRPS12), contain regulatory sequences in their 3′-untranslated region (UTR) that confers localization to the mitochondrial outer membrane, which is postulated to aid in protein translocation after translation. We show that for some mitochondrial-encoded transcripts, such as COX2, a 3′-UTR localization sequence is not required for mRNA import, whereas for corrective mitochondrial-encoded tRNAs, appending the 3′-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria. In vivo, functional defects in mitochondrial RNA (mtRNA) translation and cell respiration were reversed in two human disease lines. Thus, this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with PNPASE, with or without a mitochondrial localization sequence, providing an exciting, general approach for overcoming mitochondrial genetic disorders.

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“…These include antigenomic approaches to halt replication of mutant mtDNA or mitochondrial-targeted nucleases to selectively degrade mutated mtDNA [35]. Other strategies compensate for mutant mtDNA via allotopic expression of the wild-type genes, or via xenotopic expression of cognate genes from other species [36]. Proof of principle in cellular models has been established for most of these strategies, but there is still very limited in vivo evidence for their safety and efficacy.…”

Section: Gene Therapy To Reduce or Compensate For Mutant Mtdnamentioning

confidence: 99%

Trends in Mitochondrial Therapeutics for Neurological Disease

Leitão-Rocha¹,

Guedes-Dias²,

Pinho³

et al. 2015

CMC

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Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and agedependent mitochondrial damage, have all been connected with neurological disorders. These include not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindlechromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondria-targeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models.

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Progress and prospects: gene therapy for mitochondrial DNA disease

Cited by 72 publications

References 21 publications

Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model

Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model

Correcting human mitochondrial mutations with targeted RNA import

Trends in Mitochondrial Therapeutics for Neurological Disease

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