Mitochondrial Replacement Techniques Ethical, Social, and Policy Considerations (2016) / Chapter Skim
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FDA's Cellular, Tissue and Gene Therapies Advisory Committee met in February 2014 to discuss MRT. At this time, the FDA committee received public comments that reflected concern about certain ethical, social, and policy issues surrounding MRT.
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In accordance with the statement of task provided by FDA, the committee addressed the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed. The committee concludes that the most germane ethical, social, and policy issues could be avoided through limitations on the use of MRT or are blunted by meaningful differences between the heritable genetic modification of nDNA and that introduced by MRT.
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The committee also solicited public comments to gather expert and public opinion on such issues as the ethics of heritable genetic modification (i.e., germline modification) , patient perspectives, the role of religion, and how to conduct an ethically acceptable investigation of MRT.
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First, MRT would create embryos that if transferred would result in offspring with genetic material from two women of different maternal lineage,2 a novel intervention never before approved by U.S. federal regulatory authorities.3 Second, if MRT were carried out to conceive female offspring, the resulting mtDNA modifications would be heritable (i.e., could be passed down through generations)
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The committee also considered ethical, social, and policy concerns related to genetic modification of germ cells and the germline; unintended downstream social implications of MRT; the implications of MRT for identity, kinship, and ancestry; and the creation, manipulation, and possible destruction of human gametes and embryos that would be involved in MRT research or clinical application. The committee addressed as well the key differences between nDNA and mtDNA as they relate to the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed.
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While there is no direct modification or editing of the mtDNA sequence itself,6 this novel combination would not occur in unassisted sexual reproduction or in other assisted reproductive technologies. "Germline modification" is defined by the statement of task provided by FDA to this committee as "human inheritable genetic modification."7 Using these definitions, the committee finds that MRT results in the genetic modification of germ cells, but that it constitutes heritable genetic modification (germline modification)
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Some contend that international treaties or country-specific laws against germline modification would be violated by MRT. In the committee's judgment, although a number of ethical, social, and policy concerns have been raised about human genetic modification, whether heritable or not, through the use of MRT, these concerns warrant significant caution and the imposition of restrictions rather than a blanket prohibition on the use of MRT to prevent transmission of serious mtDNA disease.
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In the committee's judgment, there are significant and important distinctions between modification of mtDNA and nDNA that matter for an analysis of the ethical, social, and policy issues of genetic modification of germ cells and the germline: • MRT is different from any technology that could be applied to the nuclear genome in that it would entail replacement of pathogenic mtDNA with unaffected mtDNA, as opposed to targeted genomic editing of either mtDNA or nDNA. The replacement of whole, intact, and naturally occurring mitochondrial genomes represents a qualitatively different form of heritable genetic change from that resulting from any approach for modifying nDNA, which would likely involve editing rather than en bloc replacement of chromo somes -- the closest parallel to MRT.
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INITIAL INVESTIGATIONS AND GOVERNANCE OF MRT RESEARCH IN HUMANS Having addressed the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed, the committee considered the conditions and principles necessary to guide clinical investigations and oversight of MRT. Centrality of Minimizing Risk to the Future Child In discussing the benefits and risks of MRT, a weighing and balancing that would ultimately be the responsibility of FDA, the committee observed that proponents of MRT sometimes describe use of the techniques as either a preventive measure or a therapy for children with mtDNA disease.
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Because of the scientific uncertainties associated with these novel techniques and because MRT in female embryos would result in heritable genetic modification, the committee believes that a cautious approach to MRT in the U.S. research context is required, including a restriction to male embryos in initial clinical investigations.
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disease, where the mutation's pathogenicity is undisputed and the clinical presentation of the disease is predicted to be severe, as characterized by early mortality or substantial impairment of basic function. • If the intended mother at risk of transmitting mtDNA disease is also the woman who will carry the pregnancy, professional opinion informed by the available evidence determines that she would be able to complete a pregnancy without significant risk of serious adverse consequences to her health or the health of the fetus.
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should ensure that the design and conduct of initial and subsequent clinical investigations of mitochondrial replacement techniques (MRT) adhere to the following principles and practices: • The health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority in the balancing of benefits and risks with respect to the design of investi gations, eligibility of prospective mothers, numbers of participants, and pacing of investigations.
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The committee believes that its analysis can aid this ongoing discussion and that any decision about moving forward with MRT with female embryos should be informed by this discussion, and should be consistent with the established shared framework in effect at that time concerning the acceptability of techniques that result in heritable genetic modification of human embryos. Recommendation 4: Following successful initial investigations of mito chondrial replacement techniques (MRT)
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• For individuals who provide gametes, consent processes should reflect − range of MRT procedures contemplated for preclinical the and/or clinical investigations and the general ethical, social, and policy considerations surrounding MRT; − the management of incidental findings, should they arise; − appropriate compensation, with sensitivity to socioeconomic status; − prospect of future contact between individuals who pro the vided their gametes and children born as a result of MRT; and − the management of residual eggs and embryos. • For intended parents, consent processes should reflect − information on the MRT research protocol, with focus on the implications for the health and well-being of resulting children; − alternative ways of becoming parents that can avoid maternal transmission of mitochondrial DNA (mtDNA)
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overall plan for review and possible approval and subsequent market ing of mitochondrial replacement techniques (MRT) should incorpo rate the following elements: • Transparency: Regulatory authorities should maximize timely pub lic sharing of information concerning the MRT activities and deci sions within their jurisdiction.
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