Origin of the Study

On February 25-26, 2014, the U.S. Food and Drug Administration (FDA) convened a meeting of its Cellular, Tissue and Gene Therapies (CTGT) Advisory Committee to discuss “oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility” (FDA Cellular Tissue and Gene Therapies Advisory Committee, 2014). The oral comments received by FDA from members of the public at this meeting revealed substantial concern among certain commenters about the perceived ethical, social, and policy implications of the proposed techniques, which entailed issues outside the scope of the advisory committee's discussion. In response, FDA requested that the Institute of Medicine produce a consensus report addressing these issues and how they might influence the conduct of clinical investigations for MRT; the charge to the committee is presented in Box 1-1. FDA indicated that it will take the recommendations of this report into consideration in its review of future Investigational New Drug (IND) applications for clinical investigations of MRT.

BOX 1-1

Charge to the Committee.

mtDNA Disease

Mitochondria are microscopic organelles present in almost every cell type of the human body. Although they are now recognized as having myriad functions, their main role is the production of cellular energy through a process termed oxidative phosphorylation. The majority of a cell's genes and DNA are housed in its nucleus; the mitochondria contain only 37 genes, all of which encode for molecules essential to oxidative phosphorylation.

Diseases that affect the mitochondria can be caused in three ways: an individual inherits a pathogenic mtDNA mutation from its mother; an individual inherits a pathogenic nuclear DNA (nDNA) mutation from one or both parents that affects mitochondrial function; or an individual develops a de novo pathogenic mutation in either mtDNA or nDNA that affects mitochondrial function. MRT focuses only on the first type of causation—maternal transmission of pathogenic mtDNA mutations. During the process of sexual reproduction, the father's mtDNA is destroyed; only the mother's mtDNA is passed on to the child.¹ If a mother is homoplasmic for a pathogenic mutation (all of her mtDNA has the same mutation), all of her offspring will have the mutation. If a mother is heteroplasmic (some mtDNA is normal and some is mutated), her offspring will have varying levels of mutated, pathogenic mtDNA. The proportion of mutated, pathogenic mtDNA may have clinical significance, with more severe disease generally being associated with a higher percentage of mutated, pathogenic mtDNA.

Given the complexity of mitochondrial biology, mtDNA diseases can vary markedly from patient to patient; however, they are often debilitating, progressive, and fatal at a young age. Common symptoms of mtDNA disease include muscle weakness, extreme fatigue, seizures, developmental delays, heart problems, and gastrointestinal disorders. Diagnosis can be complicated, as these diseases often share symptoms with other disorders, and testing requires an integrated approach that could include metabolic, muscle, and genetic tests. The prevalence of disease-causing mtDNA mutations is difficult to estimate, but an epidemiological survey in the North East of England suggests a minimum point prevalence of 1 in 5,000 (Gorman et al., 2015).

Mitochondrial Replacement Techniques

MRT is an in vitro fertilization (IVF) technique that involves removing an intended mother's nDNA from her oocyte or zygote, which contains mutated mtDNA, and transferring it into a female provider's oocyte or zygote, which contains nonpathogenic mtDNA and from which the nDNA has been removed.² The woman providing oocytes would have no personal or family history or genetic evidence of having mutated, pathogenic mtDNA. In this report, the term “MRT” encompasses both the transfer of the nuclear genetic material and the accompanying fertilization procedure that is necessary to produce a human embryo. These techniques could allow intended mothers to produce a child that would share their nDNA without passing on their pathogenic mtDNA. Three such techniques are most advanced in development: maternal spindle transfer (MST); pronuclear transfer (PNT); and, most recent, polar body transfer (PBT). (See Chapter 2 for more detailed description of these techniques.)

Policy Landscape

As the primary regulatory authority in this area, FDA will decide whether MRT can move forward into clinical investigations, and perhaps eventually into clinical use. While FDA does not have jurisdiction over the practice of medicine in general, it can regulate certain treatments or procedures, including the use of “human cells or tissues that are intended for implantation . . . into a human” (21 CFR 1271). FDA considers standard assisted reproductive technology (ART) procedures such as IVF to be “minimal manipulation” and thus subject only to regulations aimed at the prevention of communicable disease (FDA, 2009). However, FDA considers procedures such as MST, PNT, and PBT that entail “human cells used in therapy involving the transfer of genetic material” to be more than “minimal manipulation,” and thus subject to regulation as drugs and/or biologics (FDA, 2009). In 2001, FDA advised researchers that such use of cells would require an IND, which is the first step toward clinical investigations and requires the submission of preclinical data and information on product safety, details about the technique, and proposed clinical investigation protocols.

In addition to FDA oversight, MRT research is subject to the limitations of the federal Dickey-Wicker amendment. Dickey-Wicker, included each year as a rider on the U.S. Department of Health and Human Services (HHS) appropriation bill, prohibits the use of HHS funding for research in which embryos are created for research purposes or destroyed, discarded, or subjected to risks with no prospect of medical benefit for the embryo. However, Dickey-Wicker prohibits the use of HHS funding, not the research itself, so MRT research could still be carried out with private funds, provided the technique was not prohibited or otherwise regulated by state law.

In addition, the U.S. National Academy of Sciences and the U.S. National Academy of Medicine have announced an initiative to guide decision making on gene-editing technologies. A 3-day international summit was held in December 2015, in collaboration with the Chinese Academy of Sciences and the United Kingdom's Royal Society, and an Academies consensus study has been launched to examine the scientific underpinnings of human gene-editing technologies—including potential human germline editing—and the clinical, ethical, legal, and social implications. This new Academies' effort will consider issues related to gene editing more broadly speaking, encompassing gene-editing techniques targeting nDNA and not limited to MRT or mtDNA. The consensus report of the committee conducting that study, to be released in 2016, will include findings and recommendations on the responsible use of human gene-editing research.³

Outside of the United States, the United Kingdom approved regulations to permit MRT in early 2015. The first preclinical research license for PNT was granted in the United Kingdom in 2005, and in the ensuing years, the United Kingdom's Human Fertilisation and Embryology Authority (HFEA) conducted extensive reviews of the preclinical evidence and solicited public opinion on MRT. The HFEA performed three scientific reviews to examine the safety and efficacy of MRT, looking at specific techniques and such alternatives as PGD. The HFEA's Ethics and Law Advisory Committee considered the ethical issues surrounding MRT, and the HFEA consulted and engaged in dialogue with the public through public workshops, surveys, and focus groups. In early 2014, the UK Department of Health released draft regulations for public review, and in early 2015, Parliament considered and approved revised regulations. These regulations require that MRT practitioners obtain a license from the HFEA, which will consider the specific context and techniques proposed for each license. As of late 2015, the United Kingdom was the first and only country in the world to have approved regulations to permit MRT.