Towards a therapy for mitochondrial disease: an update

Garone, Caterina; Viscomi, Carlo

doi:10.1042/bst20180134

Cited by 50 publications

(50 citation statements)

References 88 publications

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“…The current understanding that LS is caused by early-onset neurodegeneration had led to experimental treatment schemes centered around antioxidants to prevent the build-up of damaging free radicals 11,12 . However, blocking oxidative damage may not be sufficient in restoring neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanisms underlying the neurological impairment caused by SURF1 defects in humans remain poorly understood. Consequently, there are currently no pathogenicity-based treatments available for affected patients 11,12 . An important obstacle in our understanding of the disease pathogenesis is the paucity of adequate model systems 13 .…”

Section: Introductionmentioning

confidence: 99%

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SURF1 mutations causative of Leigh syndrome impair human neurogenesis

Inak

Rybak-Wolf

Lisowski

et al. 2019

Preprint

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Mutations in the mitochondrial complex IV assembly factor SURF1 represent a major cause of Leigh syndrome (LS), a rare fatal neurological disorder. SURF1-deficient animals have failed to recapitulate the neuronal pathology of human LS, hindering our understanding of the disease mechanisms. We generated induced pluripotent stem cells from LS patients carrying homozygous SURF1 mutations (SURF1 iPS) and performed biallelic correction via CRISPR/Cas9. In contrast to corrected cells, SURF1 iPS showed impaired neuronal differentiation. Aberrant bioenergetics in SURF1 iPS occurred already in neural progenitor cells (NPCs), disrupting their neurogenic potency. Cerebral organoids from SURF1 iPS were smaller and recapitulated the neurogenesis defects. Our data imply that SURF1 mutations cause a failure in the development of maturing neurons. Using NPC function as an interventional target, we identified SURF1 gene augmentation as a potential strategy for restoring neurogenesis in LS patients carrying SURF1 mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SURF1 mutations causative of Leigh syndrome impair human neurogenesis

Inak

Rybak-Wolf

Lisowski

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…As such, rapamycin inhibition of mTOR may prove beneficial in ECHS1D patients, where a similar reduction in ECHS1 expression may also activate mTOR signalling. However, rapamycin treatment can cause serious side effects, such as immune suppression and hyperlipidaemia, which need to be addressed before it is suitable for any therapeutic use [129]. 5-Aminolevulinic acid (5-ALA), in combination with sodium ferrous citrate, has also been proposed as a potential therapy for mitochondrial disease.…”

Section: Treatment Of Mitochondrial Disease and Echs1dmentioning

confidence: 99%

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Burgin

McKenzie

2020

FEBS Letters

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Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

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“…Clinical trials are currently ongoing for LHON, using rAAV‐mediated allotopic expression of ND4, which consists in the expression of a re‐engineered, normally mtDNA‐coded gene in the nucleus [81]. Because the eye is an immune‐privileged tissue, in theory, multiple doses can be given to the patient over a lifetime without worry of immune response [62].…”

Section: Viral Vectors Used To Deliver Mitochondria‐targeted Nucleasesmentioning

confidence: 99%

DNA‐editing enzymes as potential treatments for heteroplasmic mtDNA diseases

2020

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Mutations in the mitochondrial genome are the cause of many debilitating neuromuscular disorders. Currently, there is no cure or treatment for these diseases, and symptom management is the only relief doctors can provide. Although supplements and vitamins are commonly used in treatment, they provide little benefit to the patient and are only palliative. This is why gene therapy is a promising research topic to potentially treat and, in theory, even cure diseases caused by mutations in the mitochondrial DNA (mtDNA). Mammalian cells contain approximately a thousand copies of mtDNA, which can lead to a phenomenon called heteroplasmy, where both wild‐type and mutant mtDNA molecules co‐exist within the cell. Disease only manifests once the per cent of mutant mtDNA reaches a high threshold (usually >80%), which causes mitochondrial dysfunction and reduced ATP production. This is a useful feature to take advantage of for gene therapy applications, as not every mutant copy of mtDNA needs to be eliminated, but only enough to shift the heteroplasmic ratio below the disease threshold. Several DNA‐editing enzymes have been used to shift heteroplasmy in cell culture and mice. This review provides an overview of these enzymes and discusses roadblocks of applying these to gene therapy in humans.

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Towards a therapy for mitochondrial disease: an update

Cited by 50 publications

References 88 publications

SURF1 mutations causative of Leigh syndrome impair human neurogenesis

SURF1 mutations causative of Leigh syndrome impair human neurogenesis

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

DNA‐editing enzymes as potential treatments for heteroplasmic mtDNA diseases

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