Mitochondrial replacement therapy: Critical treatment or risky business?

April 10, 2015 § 3 Comments

Mitochondrial Replacement Therapy

Mitochondrial replacement therapy to stop the transmission of mitochondrial disease involves the transfer of nuclear DNA from an affected egg to a donor egg with healthy mitochondria.
Credit: Australian Science Media Centre

What are the risks associated with mitochondrial replacement therapy which is a new technique to prevent mitochondrial diseases? This was a key scientific question asked last week at a meeting held by an Institute of Medicine committee focused on the ethics and social ramifications of MRT.

At the IOM meeting, held on March 31 and April 1 in Washington, D.C., experts presented on numerous ethical, scientific, and legal topics surrounding MRT in order to inform the committee made up of twelve doctors, lawyers, and scientists. The IOM committee was commissioned by the U.S. Food and Drug Administration to explore the ethical and scientific aspects of MRT. The committee will present its findings in a report in early 2016. The spring meeting was the second of five scheduled meetings.

Mitochondrial diseases are caused by mutations or deletions in the 37 genes encoded in the mitochondrial genome. The diseases have a variety of symptoms, including muscle weakness, blindness, dementia, and some cases, childhood death. There are no cures for mitochondrial diseases.

MRT, a process in which the nuclear DNA is transferred from an affected mother’s egg to a donor egg with healthy mitochondria, is intended to stop the transmission of mitochondrial diseases from a mother to her children. The procedure is controversial because it involves destroying fertilized human eggs. Also, critics say it could lead to the slippery slope of nuclear DNA germline modification. This technique has been approved in the U.K. but is still being considered by the FDA.

The scientific presentations at the latest IOM meeting included alternatives to MRT, as well as the possible risks to the children born by MRT, such as epigenetic modifications and haplotype incompatibility. Jacques Cohen, a founder of Reprogenetics, said that pre-implantation genetic diagnosis does not work for all women with mitochondrial diseases and should not be considered a viable alternative.

Carlos Moraes at the University of Miami explained a few alternatives to MRT that reduce the proportion of mutant mitochondrial genomes. In a single mitochondrion, the two to 10 copies of mitochondrial DNA can have different genotypes. Moraes has designed a way to get restriction endonucleases to cut a defective mitochondrial genome, shifting the proportion of healthy mitochondria in cell culture. He recognized that it is not always possible to find a unique recognition sequence in a mutant genome, which is why he also is investigating other targeting systems.

Howard Hughes Medical Institute investigator George Daley at Harvard Medical School talked about potential epigenetic effects of MRT in stem cells. He admitted that epigenetic differences between different stem cell types were considerable, and techniques for analyzing single cells at an epigenetic level are limited. In short, researchers don’t know what the right epigenetic patterns are for a developing embryo, and they don’t have reliable methods to analyze the patterns either.

The fact that different mitochondrial genomes could interact poorly with different nuclear genomes was rather contentious. Doug Wallace at The Children’s Hospital of Philadelphia talked about the evolution of different groups of normal mitochondrial genomes and possible interactions between mitochondrial and nuclear genotypes. Much of his data came from subtle behavioral tests performed on inbred mice strains with swapped mitochondria. He concluded that mitochondrial DNA does influence neural performance and behavior, and that one should ensure that the mitochondrial DNA in the donor and intending mother’s eggs were as similar as possible to reduce these risks.

Cohen rebutted Wallace’s presentation by pointing out the limitations of using subtle behavioral differences in inbred mouse models to conclude anything about the highly heterogeneous human population. Direct debate was not permitted—only the committee members could question each speaker.

It will be interesting to read the committee’s report in early 2016 and see their conclusions about the risks of MRT.

Mollie Rappe

Mollie Rappe, the guest author of this blog post, is a science writing intern at ASBMB Today. You can follow her on Twitter @mollie_rappe .


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