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• W2898859854 abstract "Mitochondria are multifaceted: the “powerhouses of the cell” and integrally involved in many other cellular functions, such as autophagy and apoptosis. As a consequence, inherited or spontaneous mutations in mitochondrial genes give rise to a heterogeneous group of genetic diseases impacting multiple organs, with high-energy-demand tissues such as skeletal muscle and brain the most commonly affected. Patients with mitochondrial disease have mitochondrial DNA (mtDNA) copies with and without the harmful mutation, and it is the percentage of mutated mtDNA copies, also referred to as the “heteroplasmic ratio,” which determines disease incidence and severity. Clinical symptoms typically appear when more than 60% of mtDNA is mutated and the higher this percentage, the more severe the disease. New work suggests how this ratio might be tweaked for therapeutic benefit using gene editing technology. These reports come in the context of existing mitochondrial replacement techniques that have been developed to prevent the transmission of mitochondrial disease, in particular pronuclear transfer in which nuclear material from the woman whose eggs carry mutated mitochondria is placed in an enucleated egg from an unaffected donor. If successful, a one-cell embryo containing the nuclear DNA from the mother and father is created and can be transplanted back into the uterus. The genetic contribution from the mtDNA donor is small, constituting just 0.1% of the total DNA but this does not negate the argument that such children have a genetic and potentially legal connection to three parents (Mitalipov and Wolf, 2014Mitalipov S. Wolf D.P. Clinical and ethical implications of mitochondrial gene transfer.Trends Endocrinol. Metab. 2014; 25: 5-7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Mitochondrial replacement was approved in the UK in 2015 but has seen resistance from regulatory bodies in other countries, notably the US Food and Drug Administration (FDA; Castro, 2016Castro R.J. Mitochondrial replacement therapy: the UK and US regulatory landscapes.J. Law Biosci. 2016; 3: 726-735Crossref PubMed Google Scholar). Although babies born using such replacement therapies suggest these treatments can successfully prevent transmission of mitochondrial diseases, potential issues remain. Low levels of mtDNA mutations are carried by healthy women too and might result in mtDNA genotypic drift to the disease threshold (Floros et al., 2018Floros V.I. Pyle A. Dietmann S. Wei W. Tang W.C.W. Irie N. Payne B. Capalbo A. Noli L. Coxhead J. et al.Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.Nat. Cell Biol. 2018; 20: 144-151Crossref PubMed Scopus (104) Google Scholar). Similarly, small amounts of mtDNA carryover could also result in drift and reversion to the original genotype (Yamada et al., 2016Yamada M. Emmanuele V. Sanchez-Quintero M.J. Sun B. Lallos G. Paull D. Zimmer M. Pagett S. Prosser R.W. Sauer M.V. et al.Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes.Cell Stem Cell. 2016; 18: 749-754Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Most importantly though, the vast majority of mitochondrial diseases have no family history. Therefore, treatments are needed that aim to reduce the percentage of mutated DNA for patients after birth instead. Researchers have therefore been drawn to the prospect of mitochondrial gene editing. Mammalian mitochondria lack efficient DNA double-strand break repair pathways and Peeva et al., 2018Peeva V. Blei D. Trombly G. Corsi S. Szukszto M.J. Rebelo-Guiomar P. Gammage P.A. Kudin A.P. Becker C. Altmüller J. et al.Linear mitochondrial DNA is rapidly degraded by components of the replication machinery.Nat. Commun. 2018; 9: 1727Crossref PubMed Scopus (95) Google Scholar have recently established that the selective introduction of double-strand breaks into mutant mtDNA leads to rapid degradation of these molecules by components of the mtDNA replisome. Because mtDNA copy number is maintained in each cell at a steady-state level, the selective elimination of mutant mtDNA should stimulate replication of the remaining pool of mtDNA and produce the desired shifts in the heteroplasmic ratio. Although CRISPR is the current workhorse of gene editing, when it comes to mitochondria it does not appear to be an option. Mitochondria cannot take up the RNA strand that guides the DNA-cutting protein to the right part of the genome. Instead, the less versatile but guide-RNA-free DNA cutting approaches of the pre-CRISPR era—zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs)—can be the tools for the job. More than a decade ago, researchers showed that ZFNs can be delivered to mitochondria in cultured cells from patients and rescue the disease phenotype (Minczuk et al., 2006Minczuk M. Papworth M.A. Kolasinska P. Murphy M.P. Klug A. Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase.Proc. Natl. Acad. Sci. USA. 2006; 103: 19689-19694Crossref PubMed Scopus (121) Google Scholar). Translation of these findings in vivo was not possible until recently, however, because mouse models with heteroplasmic pathogenic mtDNA mutations had not been successfully produced. In 2016, a group used a new phenotype-driven strategy that they propose can be used to develop mice with mtDNA mutations as potential preclinical models. As proof-of-principal, they generated a mouse with a heteroplasmic mitochondrial tRNAAla gene mutation (Kauppila et al., 2016Kauppila J.H.K. Baines H.L. Bratic A. Simard M.L. Freyer C. Mourier A. Stamp C. Filograna R. Larsson N.G. Greaves L.C. Stewart J.B. A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease.Cell Rep. 2016; 16: 2980-2990Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar); this mutation resulted in tRNAAla instability and a mild cardiac phenotype, and it resembles human mtDNA mutations in tRNAAla (Reddy et al., 2015Reddy P. Ocampo A. Suzuki K. Luo J. Bacman S.R. Williams S.L. Sugawara A. Okamura D. Tsunekawa Y. Wu J. et al.Selective elimination of mitochondrial mutations in the germline by genome editing.Cell. 2015; 161: 459-469Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). Recently, two groups have taken this tRNAAla mouse model and systemically delivered mitochondrially targeted ZFNs (mtZFN; Gammage et al., 2018Gammage P.A. Viscomi C. Simard M.L. Costa A.S.H. Gaude E. Powell C.A. Van Haute L. McCann B.J. Rebelo-Guiomar P. Cerutti R. et al.Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.Nat. Med. 2018; https://doi.org/10.1038/s41591-018-0165-9Crossref PubMed Scopus (151) Google Scholar) and TALENs (mitoTALENS; Bacman et al., 2018Bacman S.R. Kauppila J.H.K. Pereira C.V. Nissanka N. Miranda M. Pinto M. Williams S.L. Larsson N.G. Stewart J.B. Moraes C.T. MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation.Nat. Med. 2018; (Published online September 24, 2018)https://doi.org/10.1038/s41591-018-0166-8Google Scholar) via adeno-associated virus. Both methods restore the molecular defect by increasing tRNAAla levels and Gammage et al. provide evidence that mitochondrial respiration improves in cardiac tissues. And importantly, increases in mtDNA deletions that can occur after double-strand breaks are not detected. The modest improvements seen in disease-associated phenotypes from both studies might reflect the relatively mild or indeed lack of disease phenotype of the tRNAAla mouse model. A model that more clearly resembles human disease is a continuing and elusive goal of preclinical research. A practical solution might be for researchers to follow the phenotypic screening method described by Kauppila et al. to see whether other models for mitochondrial disorders can be produced this way. Even without considering the challenges of delivery and dosing to humans, more robust preclinical evidence of alleviating disease phenotypes will be needed before translation to clinical studies can be considered. Unlike mitochondrial replacement techniques, these mitochondrial gene editing approaches would fall under the FDA’s gene therapy regulation and might therefore have a simpler route to gaining approval. This new evidence that virally delivered nucleases can target mutant mtDNA after birth will hopefully increase interest and activity in the field and bring new therapies for patients with these devastating and currently incurable disorders in the future." @default.
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• W2898859854 title "Mitochondria: Finding the Power to Change" @default.
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