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3.4.8 Clinical Research that Involves Heritable Changes to the Human Genome

Mitochondrial Replacement Techniques
Recommendation 3.4.8.1: 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 3.4.8.2: 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.

Heritable Genome Editing
Recommendation 3.4.8.3.1: Substantial preclinical research is needed to minimize the potential harm associated with clinical applications involving heritable genome editing; therefore, any attempt to modify the nuclear genome of human embryos for the purpose of reproduction is premature and should not be permitted at this time (see Section 2.2.3A, Category 3A, a). 

Any decision to proceed with heritable genome editing, where modified human embryos are transferred into a uterus or otherwise allowed to develop in utero, must be preceded with adequate preclinical research to minimize the potential harms from intended and unintended edits (see Recommendation 2.1.4). The first-in-human clinical uses should only be considered for the most favorable balance of potential harms and benefits and this will be most clearly defined for diseases and patients for which there are no viable alternatives. This may include prospective parents for whom there are no or very limited available alternatives for preventing transmission of diseases and conditions for which mortality is high and morbidity is severe. Other options for having a healthy child, including adoption, gamete or embryo donation, and preimplantation genetic testing, should be considered with appropriate counselling prior to any decision to proceed. 

Recommendation 3.4.8.3.2: If the technical and safety challenges associated with human heritable genome editing are resolved (see Recommendations 2.1.4 and 3.4.8.3.1), any applications for the initial clinical use of human heritable genome editing should be evaluated on a case-by-case basis. This evaluation needs to consider not just the scientific methods, but also the societal and ethical issues associated with the proposed use.  

The decision to proceed with first-in-human clinical uses needs to be taken openly with robust consideration of informed public opinion generated through meaningful public engagement. In addition, and critically, any experimental use of heritable human genome editing should only proceed in jurisdictions with appropriate and robust regulations and oversight.

A key consideration of potential uses of heritable genome editing is whether the prospective parents have feasible options for conceiving a genetically related child who does not inherit a serious genetic disease, such as preimplantation genetic testing and selection of embryos. The initial uses should be confined to prospective parents who lack reasonable alternatives.

It is important that the biological consequences of the intended genome edit are well understood, both for the immediate offspring and for future generations who might inherit it, in order to minimize the potential for an intended edit to have unintended deleterious consequences (on its own, via genetic interactions with other loci, or via environmental interactions). At present, the best way to achieve this goal is to use editing to change a known pathogenic genetic variant to one that is present in unaffected family members, common in the relevant population, or known not to be disease-causing.

Recommendation 3.4.8.3.3: A comprehensive regulatory and ethical framework for overseeing heritable genome editing must be established before any first-in-human clinical applications are considered. This framework should build on the existing regulatory frameworks for new biotechnologies, the practice of medicine, and the principles outlined in these guidelines (see Section 3.3 and 3.4). 

The regulatory framework for heritable genome editing must ensure that there is robust multi-generational follow-up to identify adverse reactions that may occur due to inherited genome alterations. However, this needs to be done in such a way as to protect the confidentiality of the prospective parents and any children born. The framework must ensure that there is a robust informed consent process that builds on the informed consent process discussed in these guidelines (see recommendations 3.4.2.5 and 3.4.4.1) and includes a discussion of potential alternative treatments (if any) and the multigenerational risks and benefits of pregnancies involving the implantation of germline genome edited embryos, including those derived from genetically modified gametes.

Recommendation 3.4.8.3.4: Regulators, research funders, and academic and medical societies should seek to prevent the premature or unethical clinical uses of heritable genome editing unless and until the safety, ethical, and societal issues associated with the clinical use of heritable genome editing are resolved. 

It is incumbent upon the entire biomedical research community to monitor for potential unethical and premature clinical uses of human heritable genome editing technologies. Researchers are strongly encouraged to report potential unethical uses to regulators, funders, licensing bodies, and academic societies to evaluate potential unethical uses of this technology. 

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