Genetic Editing of Mitochondria
Researchers at the Salk Institute have just published groundbreaking research in the journal Cell that gives hope to families who suffer from mitochondrial disorders. Mitochondria, are small organelles within our cells that serve a critical role in many cellular processes including cellular energy production and cell signaling. Originally derived from bacteria, these remarkable organelles contain their special circular DNA, which encode for 13 proteins as well as the machinery to produce them. Each mitochondrion will have 2 to 10 copies of this circular DNA. Most of the cells in our body have approximately 100 to 1000 mitochondria each though the human oocyte contains between 100,000 to 600,000 mitochondria. We inherit all of our mitochondria from our mothers. The term mitochondrial homoplasmy is used to refer to the condition when all the mitochondria have the same DNA. Mitochondria that have genetic mutations are mixed with normal mitochondria in any given cell; the term mitochondrial heteroplasmy is used. Severe and debilitating diseases (e.g. muscle weakness and blindness) can result when an individual inherits a distribution of mitochondria that favors those with a mutation. Typically disease results when the percent of mitochondria exceed a threshold in the range of 60% to 95%. Approximately 1 in 200 women are carriers of mitochondrial disease resulting in 1 in 5,000 children who are affected by diseases due to mitochondrial dysfunction. There is no effective treatment for these disorders, and classic pre-implantation genetic diagnosis is only partially effective in reducing the risk of transmission.
Recently, the UK approved a preventive therapy where the healthy mitochondria from a donor oocyte were used to replace those of a patient’s egg with risk for disease. This 3-person in vitro fertilization (IVF) has raised medical safety and ethical concerns.
In this recent report from the Salk Institute, researchers successfully used TALENs (see post on GMO babies) to repair disease causing mitochondria in mouse embryos. They also successfully used this technique to repair faulty human mitochondrial DNA that had been inserted into mouse eggs. Unlike the only current available option for prevention, this technique did not require the use of donor oocytes. The use of TALENs to correct mitochondrial DNA has the potential not only to fix the embryo being treated but also to prevent the trans-generational transmission of mitochondrial disease. The successful and safe application of this technology has great promise in preventing these diseases in current and future generations. The authors also suggest that since some germ-line mitochondrial mutations have been linked to aging, the use of this technique has the potential to prevent certain age-related diseases.
Reddy, Pradeep, et. al. Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing. Cell 161(3), 459-469. 4-23-2015.
Haas, R.H., Parikh, S., Falk, M.J., Saneto, R.P., Wolf, N.I., Darin, N., and Cohen, B.H. (2007). Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 120, 1326–1333.
Parikh, S., Saneto, R., Falk, M. J., Anselm, I., Cohen, B. H., Haas, R., and Medicine Society TM. A modern approach to the treatment of mitochondrial disease. Curr.Treat.Options.Neurol. 11(6), 414-430. 2009.
Parikh, S., et al . Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet.Med. 12-11-2014.
Tachibana, Masahito, Sparman, Michelle, Sritanaudomchai, Hathaitip, Ma, Hong, Clepper, Lisa, Woodward, Joy, Li, Ying, Ramsey, Cathy, Kolotushkina, Olena, and Mitalipov, Shoukhrat. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461(7262), 367-372. 9-17-2009.
Reinhardt, K., Dowling, D. K., and Morrow, E. H. Medicine. Mitochondrial replacement, evolution, and the clinic. Science 341(6152), 1345-1346. 9-20-2013.
Ross, J. M., Stewart, J. B., Hagstrom, E., Brene, S., Mourier, A., Coppotelli, G., Freyer, C., Lagouge, M., Hoffer, B. J., Olson, L., and Larsson, N. G. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501(7467), 412-415. 9-19-2013.
Ross, J. M., Coppotelli, G., Hoffer, B. J., and Olson, L. Maternally transmitted mitochondrial DNA mutations can reduce lifespan. Sci.Rep. 4, 6569. 2014.
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