Clinical study of mitochondrial replacement techniques for human reproduction is ethically permissible, concluded a special panel formed by the Institute of Medicine and charged by the Food and Drug Administration to study the issue.

If the FDA accepts the recommendations, issued Feb. 3, the agency could proceed with approving investigational new drug (IND) applications from U.S. research groups to test mitochondrial replacement techniques (MRTs) with the goal of allowing couples to bear children who would not inherit mitochondrial DNA diseases affecting the mother.

MRT, also termed mitochondrial transfer, involves creating an embryo with nuclear DNA from the intended mother and mitochondrial DNA from a healthy donor through modification of either an oocyte or zygote. The mitochondrial transfer techniques currently being considered are maternal spindle transfer, which uses oocytes, and pronuclear transfer, which uses zygotes. Critics of the controversial techniques have labeled MRTs as “three parent” IVF and assert that allowing their use will create a slippery slope toward enabling modification of nuclear DNA and germ-line modification.

While the IOM report , which had been in the works since late 2014, helps clear the ethical pathway to clinical testing of these novel methods, lawmakers created a new roadblock with the passage of the fiscal 2016 omnibus budget legislation, which specifically barred the FDA from using budgeted funds to evaluate proposals for therapies that involve embryo modification.

The IOM committee’s report noted that the FDA should consider approval of initial clinical investigations of MRTs “only if and when” several conditions are met, including establishment of safety and minimized risks, an adequate background of likely efficacy through preclinical research, limiting of research to women at risk for transmitting a mitochondrial DNA disease, and limiting of studies to investigators and centers with demonstrated expertise in relevant technologies.

Another key qualification the panel recommended is that initial studies be limited to male embryos so that when they become adults they would not pass their engineered mitochondrial genome to a next generation because mitochondrial inheritance occurs only via oocytes. The committee recommended that modification of mitochondrial DNA in oocytes or zygotes destined to become women be permitted in the future, but only after the procedure proved its safety in men.

The recommendations also stressed that the “health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority.”

“The main conclusion of the report is that it is ethically permissible to conduct investigations into MRT as long as significant conditions and parameters are met,” said Dr. Marni Falk , director of the mitochondrial-genetic disease clinic at the Children’s Hospital of Philadelphia and a member of the IOM committee.

Dr. Bruce H. Cohen , director of the neurodevelopmental science center and pediatric neurology at Akron (Ohio) Children’s Hospital, said he was pleased with the IOM report.

“There is nothing in the report that will stop this human research from going ahead in the United States. That’s the bottom line,” said Dr. Cohen, who has done clinical research in and drug development for children with mitochondrial disease. “They took everything into consideration, including the science and the pulse of the American public, and came up with a plan that will move this treatment forward.”

Dr. Cohen singled out the MRT research program at the Oregon Health & Science University (OHSU) as the U.S. effort closest to launching a clinical trial, and a senior research official at OHSU agreed that the panel’s recommendations represented a significant step forward.

“We feel the panel did a good job,” said Daniel Dorsa, Ph.D. , senior vice president for research at OHSU in Portland. “They put in some restrictions, such as only using male embryos to start, but that is an understandable caution. We’re pleased the report is now out because we’ve been waiting for it. We’ve been in discussions with the FDA for an IND for mitochondrial transfer for quite a while, and the FDA said that we should wait for this report.”

The OHSU research team that works on MRT, led by Shoukhrat Mitalipov, Ph.D. , already successfully used “maternal spindle transfer” to produce two macaque embryos that received donor mitochondrial DNA, said Dr. Dorsa. The two macaques remain in gestation with their delivery anticipated soon.

The next step for the OHSU group is to test the same technique with human oocytes, and they have identified several women with either Leigh syndrome or mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes ( MELAS ) who are interested in assisted reproduction using MRT.

“We’re anxiously waiting to see what the FDA will now do with the new recommendations in hand but with the congressional prohibition also in place,” Dr. Dorsa said. “With the recommendations now out, we anticipate that pressure will mount for Congress to change its position because for now U.S. women with mitochondrial DNA disease will be precluded from this cutting-edge technology that could ensure they give birth to healthy children.”

Dr. Falk cited results from a 2015 survey of 92 women with mitochondrial DNA disease or at-risk carriers of mutated mitochondrial DNA who expressed their interest in MRT. Among the 92 respondents, 21 said that they were interested in having children. Of that smaller group, 90% said they would be interested in MRT when becoming pregnant.

Dr. Falk also noted that roughly 30,000-60,000 Americans have a mitochondrial DNA disease, although many others might be affected but have never been diagnosed or undergone confirmatory sequencing of their mitochondrial DNA. In addition, many affected patients have a mutation in 1 of the 200 nuclear genes that can produce mitochondrial dysfunction and not in 1 of the 37 genes contained in mitochondrial DNA. Only women with a mutation in their mitochondrial DNA can benefit from MRT.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

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