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Mitochondrial Replacement Techniques — Implications for the Clinical Community

Marni J. Falk, M.D., Alan Decherney, M.D., and Jeffrey P. Kahn, Ph.D., M.P.H.

N Engl J Med 2016; 374:104 | February 24, 2016 | DOI: 10.1056/NEJMp1600893

Mitochondrial DNA (mtDNA) disease may be the poster child for highly targeted, “personalized” medicine. These rare disorders have well-defined genetic causes: more than 400 known pathogenic mutations or deletions in the 16,569-base-pair, mitochondrial chromosome that encodes only 37 genes. Affected persons may present at any age with some combination of severe, often progressive, and sometimes fatal neurologic, musculoskeletal, cardiac, gastrointestinal, renal, ophthalmologic, and audiologic involvement. No cures or therapies have been approved by the Food and Drug Administration (FDA) for any mtDNA disease, although symptom-based clinical management can be beneficial. 

Reproductive scientists have focused on preventing transmission by replacing the mitochondria harboring disease-causing mutations in a carrier mother’s oocytes or zygotes with mitochondria containing healthy mtDNA genomes (see diagram). Since the mtDNA genome is quarantined within mitochondria, separated from the 20,000-plus genes residing in each cell’s nucleus, it seems easiest to replace mutated mitochondria with healthy mitochondria from oocytes donated by another woman. Mitochondria are inherited only through the maternal germline, so those in an oocyte or zygote would theoretically need to be replaced only once to prevent the clinical sequelae of inherited mtDNA disease from manifesting in the child and, if that child was female, in her future offspring.

 Originally Appeared in The New England Journal of Medicine on February 24, 2016.

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