By Eli Y. Adashi, MD, MS, and I. Glenn Cohen, JD
Mitochondrial replacement therapy, an experimental approach that takes aim at maternally inherited mitochondrial diseases, is on the verge of being implemented in the United Kingdom, almost 2 years after it received approval from the UK Parliament. In a ruling issued on December 15, 2016, the UK Human Fertilisation & Embryology Authority (HFEA) concluded that mitochondrial replacement therapy “can be used cautiously for risk reduction treatments in certain cases where alternative treatments would be of little or no benefit to mothers at risk of passing mitochondrial disease onto their children.”
These disorders, which are frequently fatal, are caused by mutations in mitochondrial DNA (mtDNA) that are passed from mother to offspring. Although these disorders are incurable, researchers believe it now may be possible to prevent them by mitochondrial replacement therapy, combining the nucleus from the egg of an affected woman with the cytoplasm from an unaffected woman that contains healthy mitochondria.
Safety concerns include the possibility of a mismatch between donor and recipient and the possibility that some mutant mtDNA will be transferred along with the nucleus and multiply sufficiently to cause disease. Other, more ethical, concerns focus on the notion of germline-modified offspring of “3-membered” parentage.
A US Ban
Although the United Kingdom has decided to move forward with mitochondrial replacement therapy, the circumstances in the United States could not be more different. On this side of the Atlantic, a 10-line provision in an enormous congressional spending bill bans the evaluation of mitochondrial replacement therapy by the US Food and Drug Administration (FDA). The implications are obvious: absent an FDA ruling on the safety and efficacy of mitochondrial replacement therapy, clinical application is and remains impermissible.
This ban, which comprises Section 749 of the Consolidated Appropriation Act of 2016, precludes the FDA from evaluating “research in which a human embryo is intentionally created or modified to include heritable genetic modification.” It also specifies that “none of the funds made available by this Act [to the FDA] may be used to review or approve an application for an exemption for investigational use of a drug or biological product” for such research.
The provision further states that even if researchers submit relevant Investigational New Drug (IND) applications to the FDA, the applications “shall be deemed to have not been received by the Secretary [of Health and Human Services], and the exemption may not go into effect.” Effective initially through fiscal-year 2016, the ban has since been extended twice through April 28, 2017.
The congressional record is mum on the identity of the sponsor or sponsors of the ban, and the precise motives for crafting it remain equally uncertain. The ban’s enactment was all but guaranteed by the complete absence of discussion before its passage or at any time thereafter, and by its inclusion in a must-pass omnibus appropriation bill.
The institution of clinical or research bans on the exploration of innovative technologies is hardly a novelty. If recent history is any guide, appropriation-dependent or appropriation-independent bans have been considered, and in some cases implemented, including human embryo research, xenotransplantation, human embryonic stem cell research, human fetal research, germline gene therapy, reproductive cloning, recombinant DNA technology, gene drives, genetically modified food, and others. The moratorium on mitochondrial replacement therapy constitutes an appropriation-dependent policy rider that has to be annually renewed to remain in effect. Although this moratorium is embedded in statute, it cannot be viewed as permanent, as it would be if it had passed as an amendment to the Food Drug and Cosmetic Act, for example.
Whether one supports or opposes the ban on mitochondrial replacement therapy, there is no denying that it precludes affected families from pursuing what could well be a life-saving technology for future offspring. Indeed, for those affected or at-risk, mitochondrial replacement therapy represents the only hope for ensuring a genetically related healthy offspring. An estimated 12 423 women in the United States are at risk of transmitting mitochondrial DNA disease, and they are currently without recourse within US borders.
Although cross-border care may constitute an option for some US women who might benefit, this solution is hardly applicable to all. Thus far, only one case of cross-border mitochondrial replacement therapy has been reported to have been carried out, by a US-led team in Mexico. Recent legislative initiatives in Mexico now suggest that mitochondrial replacement therapy may be banned there as well. The extent of women seeking the treatment in the United Kingdom remains to be seen. For now, one can only hope that a “government of the people, by the people, for the people” can, shall, and will reconsider.
About the authors:
Eli Y. Adashi, MD, MS, is a professor of Medical Science and the former dean of Medicine and Biological Sciences at the Warren Alpert Medical School of Brown University in Providence, Rhode Island. (Image: Brown University)
I. Glenn Cohen, JD, is a professor of Law and director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, Cambridge, Massachusetts. (Image: Martha Stewart)
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