On February 3, 2016, the Institute of Medicine (IOM) released its Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases report.1 Commissioned by the US Food and Drug Administration (FDA), the report provides important information for the agency, which is considering the approval of mitochondrial replacement therapy for the prevention of mitochondrial DNA diseases.1 Expansive in its purview and thorough in its scrutiny, the report concludes that it is “ethically permissible” to embark on clinical trials involving human beings, subject to rigorous safety and efficacy imperatives.1 The report further recommends that initial clinical trials be limited to male embryos whose mitochondria cannot be transmitted to their progeny.1 In so doing, the IOM is seeking to preclude transmission of unintended outcomes to the progeny.1 In an unforeseen turn of events, the release of the IOM report was preceded by the enactment of a federal statute that prohibits the FDA from considering research applications for the conduct of this therapy.2 This Viewpoint seeks to contextualize the IOM report by describing the drive to bring mitochondrial replacement therapy to the clinic and the statutory constraints blocking its adoption. Mutant mitochondrial DNA of maternal origin fosters numerous inborn errors of metabolism.3 Cure of those affected remains unattainable.3 In addition, preimplantation risk stratification is compromised by the complexities of mitochondrial DNA segregation.3 However, mitochondrial replacement therapy could lead to the possibility of disease-free births in lineages at risk.3 In the United Kingdom, the House of Commons voted to approve the substitution of mutant oocytic or zygotic mitochondrial DNA with a donated wild-type counterpart.4 In other words, restoring the function of affected mitochondria by replacing abnormal DNA with a donated normal variety. The House of Lords followed suit.4 Early clinical trials in the United Kingdom could commence this year. In the United States, regulatory efforts to adjudicate mitochondrial replacement therapy date back to 2014 when the Cellular, Tissue, and Gene Therapies Advisory Committee of the FDA first convened.5 The attendant exploratory discussion of “oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility” was not followed by a vote.5 Shortly thereafter, the IOM report was commissioned. Viewed collectively, these developments are nothing short of historic and their significance multifaceted. First, mitochondrial replacement therapy represents the sole example of state-approved germline gene therapy in the human. Second, it comprises the only known intervention with the potential to reduce the burden of mitochondrial DNA diseases. Third, it constitutes the first case in which organelle and, indeed, whole cytoplasmic cellular replacement are being contemplated. Fourth, it irrevocably alters assisted reproduction by placing it at the center of future genome editing efforts. Fifth, it acts as a test case for the regulatory adjudication of other emerging reproductive innovations. Examples include but are not limited to editing the genome of the human embryo and the prospect of using somatic (eg, skin) cells to generate eggs and sperm in a laboratory dish. The above notwithstanding, mitochondrial replacement therapy remains the focus of safety, ethical, and legal concerns.1,3 All have been carefully considered by the IOM report.1 Safety concerns focus on the possibility of mitochondrial-nuclear incompatibility previously noted in a number of (nonhuman) experimental models.1,3 Preprocedural matching of the mitochondrial haplotypes of the donor and the recipient may thus be required.1,3 Ethical and legal concerns stem from the establishment of a "tri-parental" unit wherein the parental status of the donor is open to varied interpretations.1,3 The development of donor-independent mitochondrial replacement therapeutic alternatives is therefore called for.1,3 Preliminary feasibility studies hold out hope for just such possibility.1,3,6 In an unexpected development, President Obama signed into law a policy rider that precludes modification of the human germline.2 Incorporated under section 749 of the Consolidated Appropriation Act of 2016,2 the rider directs the FDA to refrain from considering “applications for an exemption for investigational use…in research in which a human embryo is intentionally created or modified to include heritable genetic modification.” Possibly targeted at the prospect of editing the genome of a human embryo, the rider, nevertheless, is equally applicable to mitochondrial replacement therapy.2 This conclusion has been affirmed by an agency spokesperson who said that the FDA has resolved to delay on the adjudication of mitochondrial replacement therapy for the rest of the current fiscal year.7 In so doing, the FDA appears to have concluded that the recommendation of the IOM report to limit initial intrauterine transfers to male embryos will not comply with the rider, the absence of “heritable genetic modification” notwithstanding.7 Although not referenced in the final version of the Consolidated Appropriation Act of 2016, the IOM’s recommendations were quite evident in early versions of the bill.8 In a June 17, 2015, draft of the House appropriation bill (HR 3049), the FDA was directed to “establish an independent panel of experts, including those from faith-based institutions with expertise on bioethics” to “review the IOM report.”8 The panel of experts was further tasked with reporting its “conclusions, along with any recommendations…to the Committee [on Appropriations] within 30 days of the completion of the report by the IOM.”8 Even though this directive was never enacted, it suggests that Congress would like to have an FDA panel of experts further review a report that the agency commissioned in the first place. Of further note is the observation that the IOM report targeted for evaluation was commissioned from the National Academy of Sciences, which were established by an Act of Congress to advise the government “whenever called upon” by any government department.9 One important step forward was taken by the IOM report when it concluded that it is “ethically permissible” to embark on first-in-human clinical trials of mitochondrial replacement therapy subject to rigorous safety and efficacy imperatives.1 In so doing, the report lends substantial moral support to those affected and to advocates of mitochondrial replacement therapy. However, progress was impeded with the enactment of a policy rider that precluded the FDA from further consideration of mitochondrial replacement therapy.2 Running counter to the moral doctrine of beneficence, this recent development is hardly without consequences. Those affected, estimated to be approximately 800 US women per year, will not be in a position to explore the promise of mitochondrial replacement therapy. The likelihood that the policy rider will be repealed at some point in the future cannot be readily ascertained. The durability of related policy riders does not bode well for such contingency. For instance, the Dickey-Wicker Amendment (which prohibits public funding of human embryo research) has just marked its 20th anniversary, and the Hyde Amendment (which prohibits public funding of abortions) is rapidly approaching 40 years as a policy rider. It follows that the implementation of mitochondrial replacement therapy in the United States most likely will be an uncertain proposition for some time to come. Whether the eventual births of disease-free children in the United Kingdom will change congressional hearts and minds remains to be seen. Failing such, progress in the prevention of mitochondrial DNA diseases will remain the domain of a biomedical enterprise an ocean away. Back to top Article Information Corresponding Author: Eli Y. Adashi, MD, MS, the Warren Alpert Medical School, Brown University, 101 Dudley St, Providence, RI 02905 (email@example.com). Published Online: June 9, 2016. doi:10.1001/jama.2016.4930. Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: Mr Cohen is supported by the Greenwall Foundation Faculty Scholar in Bioethics Award. Role of the Funder/Sponsor: Greenwall Foundation had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. References 1. National Academies of Sciences, Engineering, and Medicine. Mitochondrial replacement techniques: ethical, social, and policy considerations. http://iom.nationalacademies.org/reports/2016/Mitochondrial-Replacement-Techniques. February 3, 2016. Accessed March 27, 2016. 2. Consolidated Appropriations Act of 2016. Pub L N. 114-92. §749. https://www.congress.gov/bill/114th-congress/house-bill/2029/text. December 18, 2015. Accessed March 27, 2016. 3. Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing mitochondrial disease: what is new and what challenges remain? Science. 2015;349(6255):1494-1499.PubMedGoogle ScholarCrossref 4. Kmietowicz Z. UK becomes first country to allow mitochondrial donation. BMJ. 2015;350:h1103.PubMedGoogle ScholarCrossref 5. US Food and Drug Administration. Cellular, Tissue, and Gene Therapies Advisory Committee meeting: announcement. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm380042.htm. February 25-26, 2014. Accessed March 27, 2016. 6. Reddy P, Ocampo A, Suzuki K, et al. Selective elimination of mitochondrial mutations in the germline by genome editing. Cell. 2015;161(3):459-469.PubMedGoogle ScholarCrossref 7. Brennan Z. Expert committee: FDA should allow mitochondrial replacement trials under certain conditions. http://raps.org/Regulatory-Focus/News/2016/02/03/24245/Expert-Committee-FDA-Should-Allow-Mitochondrial-Replacement-Trials-Under-Certain-Conditions. Posted February 3, 2016. Accessed March 27, 2016. 8. House Report 114-205—Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Bill, 2016. http://thomas.loc.gov/cgi-bin/cpquery/?&dbname=cp114&sid=cp114b23IJ&refer=&r_n=hr205.114&item=&&&sel=TOC_216414&. Accessed March 27, 2016. 9. National Academy of Sciences. Mission. http://www.nasonline.org/about-nas/mission/?referrer=https://www.google.com/. Accessed March 27, 2016.
JAMA – American Medical Association
Published: Jul 19, 2016
Keywords: dna, mitochondrial,inborn errors of metabolism,institute of medicine (u.s.)