Mitochondrial Replacement Techniques (MRT)
This page assembles the sections of the Guidelines that specifically address research involving mitochondrial replacement techniques. Other sections of the Guidelines may be relevant to such research (e.g., Section 2.1 Review Process, Section 2.3 Procurement and Informed Consent of Human Biological Materials, and Chapter 3. Clinical Translation of Stem Cell-based Interventions).
2.2.2 Category 2
2.2.2 Category 2. Forms of research with embryos, certain chimeras, and stem cell-based embryo models that are permissible only after review and approval through a specialized scientific and ethics review process. A comprehensive review should be coordinated with other relevant oversight, such as that provided by human subjects review committees, in vitro fertilization (IVF) clinic oversight bodies, and animal research review processes (see 2.2.1), and the research should comply with local law and policy. All such research should have a compelling scientific rationale and necessitate the use of these materials rather than employ alternative models. The research should use the minimum number of embryos necessary to achieve the scientific objective. Forms of research requiring comprehensive review by a specialized review process encompass the following activities:
Transferring human embryos to a human uterus following mitochondrial replacement.
Mitochondrial Replacement Techniques
Recommendation 188.8.131.52: Further research should be undertaken to refine and assess the safety and efficacy of Mitochondrial Replacement Techniques (MRT), including minimizing a) the risk of mitochondrial carryover and b) disruptions to the interaction between mitochondrial and nuclear genomes. In addition, further research on polar body transfer techniques and the use of mitophagy or genome editing is needed to reduce or eliminate pathogenic mitochondrial DNA. Such research should be subject to review by a specialized oversight process as Category 2 Research (Section 184.108.40.206).
MRT is being explored to prevent the transmission of serious mitochondrial DNA-based diseases in at-risk pregnancies (see Section 3.4.8). MRT most commonly involves transferring the nuclear DNA from the prospective mother’s oocyte or fertilized oocyte (pronuclear stage) to that of a mitochondrial donor from which the nuclear DNA has been removed [maternal spindle transfer (MST) or pronuclear transfer (PNT), respectively]. The mitochondrial donor is selected to be free of known pathogenic mutations. Input from clinicians and scientists with relevant expertise in mitochondrial and embryo biology should augment the review process for evaluating clinical protocols that entail uterine transfer of human embryos for the purpose of human reproduction.
2.2.3 Category 3
2.2.3A Category 3A. Research activities currently not permitted. Research under this category should not be pursued at this time because the approaches are currently unsafe or raise unresolved ethical issues. There may be valid reasons for undertaking the research in the future, but this should not proceed until the safety and ethical issues are resolved. Such research includes:
Research in which human embryos that have undergone editing to their mitochondrial genome are transferred into or gestated in a human uterus, as current knowledge of such interventions is inadequate to ensure safety.
3.4.8 Clinical Research that Involves Heritable Changes to the Human Genome
Mitochondrial Replacement Techniques
Recommendation 220.127.116.11: Mitochondrial Replacement Techniques (MRT) should be offered only in the context of clinical investigation that is subject to strict regulatory oversight, limited to patients at high risk of transmitting serious mitochondrial DNA-based diseases to their offspring, when no other treatments are acceptable, and where long-term follow-up is feasible. International data sharing arising from initial uses is essential to help inform the field and ensure its appropriate use.
Initial applications of MRT should continue to be restricted to cases in which the probability of transmission of pathogenic mitochondrial DNA is very high, where preimplantation genetic testing is unlikely to identify embryos suitable for transfer, and where procedures are conducted in the context of clinical investigation that can contribute to generalizable knowledge about this currently unproven and experimental technique. Preclinical research in human embryo-derived stem cells following MRT indicated the possibility of levels of maternal mitochondrial DNA increasing with extended passaging, but the clinical relevance of these data is unclear. Concerns have also been expressed about the possibility of mito-nuclear interactions being disrupted by MRT, though these remain theoretical. Research on embryonic stem cells derived from embryos after MRT or on the embryos themselves maintained in vitro would help explore these issues. These experiments could only proceed in jurisdictions where the creation of embryos for research is allowed, and only where they have been permitted following review by a specialized oversight process (see Section 2.1).
Recommendation 18.104.22.168: There are inadequate clinical and preclinical data to justify the use of MRT to treat unexplained infertility associated with poor oocyte/embryo quality in women; therefore, it is recommended that this not be an intervention at this time.
MRT has been used in the clinic as a speculative treatment for infertility (Zhang et al 2016). Given the risks entailed and the absence of clear mechanisms and compelling rationale for the use of MRT for unexplained infertility, additional preclinical and clinical experience are required to establish safety and efficacy. In one reported pilot trial of MRT, embryonic development and pregnancy rates in patients of advanced maternal age did not increase (n= 30), and it was advised that such patients should not undergo MRT (Mazur, 2019). Data from another small (non-randomized) trial of MRT (n= 25), in women under 40 with previous multiple failures of IVF (Costa-Borges et al, 2020), suggest that further controlled trials and follow-up are required. Research conducted in vitro to understand the mechanism by which application of the techniques may help unexplained infertility (which might not involve mitochondria) should be conducted, notably because this may lead to alternatives that both circumvent the use of technically challenging methods and avoid any risks associated with heteroplasmy or disrupted mito-nuclear interactions.