Tuesday, February 9, 2016

Mitochondrial replacement

A new consensus report issued by the Institute of Medicine finds that research into mitochondrial replacement techniques (MRTs), where an embryo has genetic information from three people, is "ethically permissible," and should be allowed to move forward under limited conditions.

The US Food and Drug Administration (FDA) requested the report on the ethical, social, and policy considerations related to MRT to advise its decision whether to sanction such research in the United States.

If MRT is effective, it would allow women with mitochondrial DNA (mtDNA) disease to have genetically related children without passing on their mtDNA diseases. The technology represents a unique opportunity for a small group of patients, explained Marcelle Cedars, MD, from the University of California, San Francisco, in an interview with Medscape Medical News.

Dr Cedars suggested that physicians understand the basis for MRT so that "they don't perpetuate this sense of sort-of three-parent reproduction."

For the women with mitochondrial disease, this the only path for them to have their own genetic children. Dr Cedars explained that, as a reproductive endocrinologist, she sees first-hand the primal instinct to have a family. MRT may extend the opportunity to reproduce to yet another group of people, while at the same time improving human health...

The Institute of Medicine (IOM) committee clearly distinguished between modification of mtDNA and modification of nuclear DNA. MRT does not involve targeted editing of the nuclear genome. In addition, MRT will be limited to women with mtDNA disease and limited to the purpose of giving birth to a healthy child.

"The US has been fairly conservative about a lot of embryo research and embryo manipulation," explained Dr Cedars. She added that sometimes people make slippery slope arguments suggesting that if you alter mtDNA now, maybe the technique will be used in the future to optimize for a trait such as athletic performance or cognition. She feels that these arguments are not justifiable and that, in reality, genetic engineering is not used for such purposes.

Although the IOM acknowledged concerns about MRT, specifically recognizing the fact that MRT is new and the effects are currently unknown, they conclude that most of these concerns could be avoided by limiting its use. In particular, the committee made recommendations designed to minimize the risk for harm to the child born as a result of MRT.

Because the technique is not yet available clinically, the committee recommended that studies be performed to determine the safety and efficacy of MRT. The committee also suggested that all investigations of MRT pay special attention to consent in research, as well as communication of the novel aspects of MRT research to potential participants.

Furthermore, the IOM committee suggested that clinical investigations be limited to women who are at risk of transmitting serious mtDNA disease. In addition, only male embryos should be transferred for gestation.
Mitochondria are passed from the mother, so limiting the technique to male embryos would avoid introducing heritable genetic modifications into the human population. Such an approach would thus limit the effect on future generations.

"It's very exciting and a potential way to treat a very serious disease," enthused Dr Cedars. Limiting initial efforts to boys also represents a middle-of-the road approach, she explained.

Should initial investigations of MRT prove successful, the committee recommended that the FDA consider extending MRT research to the transfer of female embryos...

MRT was approved in the United Kingdom last year.

At that time, medical ethicist Art Caplan, PhD, from the New York University Langone Medical Center in New York City, provided some perspective for Medscape Medical News. "There certainly is room to debate where we want genetic engineering to go. I would argue that mitochondrial transplant is the wrong place to draw the line. Preventing parents who want to try to have a healthy child who can live does not seem to be the right place to say no to this form of genetic engineering."


See:  http://childnervoussystem.blogspot.com/2015/02/babies-with-3-genetic-parents.html


  1. An experimental assisted reproduction technique that could allow some families to avoid having children with certain types of heritable disease should be allowed to go forward in the United States, provided it proceeds slowly and cautiously. That is the conclusion of a report released today from a panel organized by the U.S. National Academies of Sciences, Engineering, and Medicine (NAS), which assesses the ethics questions surrounding the controversial technique called mitochondrial DNA replacement therapy. (Some of the panel also summarizes the deliberations in a Policy Forum in Science.)

    More controversially, however, the panel recommended that only altered male embryos should be used to attempt a pregnancy, to limit the possible risks to future generations. (Males can’t pass along the mitochondrial DNA that is altered in the procedure.)...

    Scientists have developed ways to transfer the genetic material from an egg with faulty mitochondria into a healthy egg, either before or just after fertilization. Such techniques, called mitochondrial DNA replacement therapy (MRT), could in theory allow women who are carriers of mitochondrial disease to have genetically related children. (Current options include adoption or using an egg donor.)

    The embryo resulting from MRT carries DNA from three people: nuclear DNA from the couple undergoing treatment and mitochondrial DNA from the healthy egg donor. The prospect of such “three-parent embryos,” along with the fact that any offspring would pass their mitochondrial genes on to their own children, has made the technique controversial. So the U.S. Food and Drug Administration (FDA) asked for the review as part of its deliberations about whether to allow researchers in the United States to use the technique. (continued)

  2. (continued)MRT’s potential benefits outweigh the problems, the NAS committee says, provided that work proceeds slowly. That means only the women who are considered very likely to pass on severe forms of mitochondrial disease should be candidates for the first clinical attempts.

    In addition, to avoid the possibility that babies born via MRT would pass unforeseen problems along to their own children, the panel also recommended that only male embryos be used to start a pregnancy...

    The committee strongly recommends that any studies be designed so that results from multiple studies can be combined to learn as much as possible about the safety of the techniques. They also recommend that any children born via MRT be followed by researchers over the long term, so any physical or even psychological effects could be better understood. That requires permission from the parents at first, but would later require permission from the children themselves once they are old enough. That’s a challenge, Kahn says. “You can’t give consent for people who have not yet been conceived.”

    The panel also encourages FDA to consider carefully how they can prevent other possible uses of the technique. Some researchers have proposed using MRT to treat age-related infertility, for example, but that is not ethically justified, the committee says.

    That’s a potential problem, says Marcy Darnovsky, executive director of the Center for Genetics and Society, and advocacy group in Berkeley, California, that has opposed approval of MRT. “It’s important to realize that if the FDA were to approve these techniques, it would have few mechanisms for preventing what would essentially be ‘off-label uses,’” Darnovsky says in a statement. “One U.S. proponent of these techniques has already made it publicly clear that he would like to expand their use widely to fertility clinics. Their use could easily spin out of control.”...

    After years of scientific and ethical debate, the United Kingdom passed a law last year that would allow fertility clinics there to offer the technique—but on a case-by-case basis and closely overseen by that country’s Human Fertilisation and Embryology Authority (HFEA), which regulates assisted reproduction and embryo research. No clinics have yet received approval to use the technique there.

    The United States does not have an equivalent to HFEA, but FDA has said that anyone who wants to use the technique needs to apply to the agency for permission, because MRT is a form of gene therapy. In 2014, it started a process to assess the scientific and ethical questions surrounding the technique. The NAS report will help shape FDA’s decision on regulations and guidelines for such applications.

    But don’t expect any such experiments to proceed quickly in the United States. Federal legislation passed in December limits the agency’s ability to grant permission for any mitochondrial replacement therapy efforts for fiscal year 2016. Because of the legislation, a FDA spokesperson noted in an email, “the agency will not receive or review INDs [Investigational New Drug applications] for human subject research utilizing genetic modification of embryos for the prevention of transmission of mitochondrial disease in FY 2016 and human subject research using these technologies cannot be conducted in compliance with the Federal Food, Drug, and Cosmetic Act and FDA’s implementing regulations.”