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Developmental biology - Mitochondrial DNA Transfer|
Mitochondrial replacement to prevent disease?
Mothers with mitochondrial DNA mutations often give birth to children who face incurable and fatal illnesses. But, researchers advocate a much-studied form of Mitochondrial Replacement (MR) which could prevent transmission of such diseases from mothers to children. For this reason, two researchers argue that the U.S. moratorium that includes MR should be reconsidered in a process engaging the public, medical professionals, the U.S. Food and Drug Administration and Congress.
The mitochondrial replacement moratorium should be reconsidered, say professors from Brown University Medical School and Harvard Law School. The professors urge the US to allow for the replacement of mutation-bearing mitochondria to prevent fatal illnesses in children.
The authors - Eli Adashi, a professor of medical science at Brown University's Warren Alpert Medical School, and Harvard Law School professor I. Glenn Cohen, present their case in the March 2018 commentary in Obstetrics & Gynecology.
Such a process could benefit the births of healthy children, as well as eliminate the concern about genetic editing of embryos. MR therapy simply replaces mutation-bearing mitochondria in unfertilized and un-implanted eggs with donated mitochondria.
"A thousand children are born every year in the U.S. with serious, life-threatening issues that in a better world could be prevented by mitochondrial replacement. While I have every respect for the sanctity of life, this issue is not about the sanctity of life. There is an inherent hypocrisy in holding this procedure hostage at the expense of 1,000 children each year who are doomed to die a painful death. There is nothing anti-life about the procedure, because no embryo is destroyed, and the life of baby is saved."
In 2016, legislation was passed that prohibits U.S.-based research in which a human embryo is intentionally created or modified, the study notes. While MR does not modify or "enhance" the nuclear genome, according to Adashi, replacing mutation-bearing mitochondria with donated mutation-free mitochondria falls under the general category of procedures prohibited by the moratorium.
In their commentary, Adashi and Cohen point out that the authors of the legislation are anonymous and that no congressional hearings, floor discussions or public engagement took place before its passage.
The authors surmise that the legislation may have been intended primarily to prevent embryo loss, a concern that does not apply to MR. A public process of reevaluating MR's inclusion in the moratorium could help to clarify that MR takes place before an embryo exists. Donated mitochondria are placed within unfertilized eggs, and can then be fertilized so that women can give birth to genetically related, disease-free children.
Adashi believes it is possible that a misunderstanding of the sweeping nature of the legislation inadvertently bars the procedure.
Impact of the moratorium
Mitochondrial diseases include Leigh syndrome, a progressive and fatal disorder characterized by lesions on the brain that may lead to heart, kidney, vision and breathing complications. Alpers Disease is a neurologic illness that causes seizures, dementia, spasticity, blindness, liver dysfunction and cerebral degeneration.
The moratorium may induce American families to seek care outside of the country, according to Adashi and Cohen, noting that a U.S. led team in Mexico may have prevented Leigh syndrome in a child by replacing the mutation-bearing mitochondria of oocytes with donated mutation-free oocytes.
"This development calls into question the regulatory utility of a national moratorium in a globalized world wherein cross-border care is increasingly prevalent," Adashi and Cohen wrote in their study. It also creates risks, the authors assert, because there is no FDA oversight of these procedures that take place outside the U.S. border. Thus, the authors contend, the moratorium deprives affected American families of the opportunity to prevent inherited, incurable and agonizing mitochondrial disease in their children.
A path forward
Adashi and Cohen recommend that a coalition of patient and advocacy groups, medical professionals and legislators convene congressional hearings on the prevention of mitochondrial diseases. They also suggest convening a public meeting of the FDA's Cellular, Tissue and Gene Therapies Advisory Committee, charged with regulating reproductive technologies, to review the state-of-the-art procedure.
They also recommend stringent FDA oversight, the conditional approval of biologic licensing applications, clinic-specific licensing, possible sunset contingency provisions, and long-term intergenerational follow-up of the children of mothers who undergo mitochondrial replacement to determine the continuing safety and efficacy of the intervention.
In the U.K., a careful 15-year vetting process resulted in a vote in Parliament that approved MR under stringent regulatory oversight.
In the U.S., on the other hand says Adashi: "Congress legislated a statute that prohibits the FDA from adjudicating research into a range of procedures hereby treating the issue with a broad brush. They spent 15 years studying it - the science, the safety, the ethics - and they asked the British public what they thought. Now MR is legal but regulated by an agency that has been proceeding very cautiously, with just one clinic licensed to perform the procedure."
What this means, explains Adashi, is that parents who are at risk for transmitting mitochondrial disease to their children can now undergo MR and have children who are not born with agonizing and untreatable diseases. American parents, Adashi and Cohen write, deserve nothing less.
In a possible first, the heritable transmission of a fatal mitochondrial DNA disease (Leigh syndrome) may have been prevented by replacing the mutation-bearing mitochondria of oocytes with donated mutation-free counterparts. The procedure, carried out by a U.S.-led team, took place in Mexico in circumvention of a statutory U.S. moratorium on mitochondrial replacement. This development calls into question the regulatory utility of a national moratorium in a globalized world wherein cross-border care is increasingly prevalent. This development also calls to account the moral defensibility of a moratorium that acquiesces in the birth of gravely ill children whose afflictions could have been prevented. In this Current Commentary, we outline a potential path forward by analyzing the dual imprint of the moratorium, examining its legislative shortcomings, exploring its motivational roots, considering its national effect, and proposing its unlinking from the related yet distinct ban on editing the genome of the human embryo.
Authors: Eli, Y. Adashi; Glenn I. Cohen.
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Mitochondrial donation therapy, could allow babies to be conceived with genetic material from three individuals. Image: Ben Birchall/PA via The Guardian.