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Heritable Human Genome Editing (2020) / Chapter Skim
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Summary
Pages 1-18

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From page 1...
... HHGE could represent an important option for prospective parents with a known risk of transmitting a genetic disease to have a genetically-related child without that disease and its associated morbidity and mortality. However, it will be essential to establish safe and effective methodologies that could form the necessary steps in a translational pathway for any clinical uses of HHGE.
From page 2...
... are or could be sufficiently well developed to permit responsible clinical use of HHGE; identifies initial potential applications of HHGE for which a responsible clinical translational pathway can currently be defined; and delineates the necessary elements of such a translational pathway. It also elaborates national and international mechanisms necessary for appropriate scientific governance of HHGE, while recognizing that additional governance mechanisms may be needed to address societal considerations that lie beyond the Commission's charge.
From page 3...
... Recommendation 3: It is not possible to define a responsible translational pathway applicable across all possible uses of heritable human genome editing (HHGE) because the uses, circumstances, and considerations differ widely, as do the advances in fundamental knowledge that would be needed before different types of uses could be considered feasible.
From page 4...
... Recommendation 6: Any proposal for initial clinical use of heritable human genome editing should meet the criteria for preclinical evidence set forth in R ­ ecommendation 5. A proposal for clinical use should also include plans to evaluate human embryos prior to transfer using: •  developmental milestones until the blastocyst stage comparable with standard in vitro fertilization practices; and •  biopsy at the blastocyst stage that demonstrates a o  existence of the intended edit in all biopsied cells and no evidence the of unintended edits at the target locus; and o  evidence of additional variants introduced by the editing process at no off-target sites.
From page 5...
... . The ISAP should have a diverse, multidis ciplinary membership and should include independent experts who can assess scientific evidence of safety and efficacy of both genome editing and associated assisted reproductive technologies.
From page 6...
... that go beyond the translational pathway defined for initial classes of use of HHGE, an international body with appropriate standing and diverse expertise and experience should evaluate and make recommenda tions concerning any proposed new class of use. This international body should: •  clearly define each proposed new class of use and its limitations; •  enable and convene ongoing transparent discussions on the societal i ­ssues surrounding the new class of use; •  make recommendations concerning whether it could be appropriate to cross the threshold of permitting the new class of use; and •  provide a responsible translational pathway for the new class of use.
From page 7...
... ­ lthough A the pace of advances in developing genome editing methodologies continues to be rapid, and ongoing research to overcome current scientific and technical challenges will continue to be valuable, significant knowledge gaps remain concerning how to control and characterize genome editing in human zygotes, as well as in the development of potential alternatives to zygote editing. Gaps that would need to be addressed include the following: Limitations in the Understanding of Genome Editing Technologies.
From page 8...
... IMPORTANCE OF SOCIETAL DECISION MAKING ABOUT HERITABLE HUMAN GENOME EDITING This report focuses on whether a responsible translational pathway can be defined for some potential applications of HHGE. However, it is important to emphasize that the existence of a responsible clinical translational pathway does not mean that a clinical use of HHGE should proceed.
From page 9...
... It is not possible to perform a generic benefit–harm analysis covering all possible applications of HHGE since any assessment will depend on the particular circumstances under consideration. One overarching principle that guided the Commission in identifying circumstances for which a responsible translational pathway could be defined was that the highest priority should be given to safety, with any initial uses offering the most favorable balance of potential harms and benefits.
From page 10...
... A TRANSLATIONAL PATHWAY FOR HERITABLE HUMAN GENOME EDITING By a translational pathway for HHGE, the Commission means the steps that would be needed to enable a proposed clinical use to proceed from preclinical research to application in humans. The framework proposed by
From page 11...
... SCIENTIFIC VALIDATION AND STANDARDS FOR ANY PROPOSED USE OF HERITABLE HUMAN GENOME EDITING The initial use of HHGE would represent a new technological intervention in the ART clinic, with only preclinical data with which to judge efficacy and safety. The goal of setting technical standards for HHGE would be to provide very high confidence that any transferred embryos would be correctly edited and that these embryos would have no additional potentially harmful changes introduced by the editing process.
From page 12...
... Beyond Commission's remit with any further clinical uses FIGURE S-1  The main elements of a clinical translational pathway for a proposed use of HHGE to enable parents to have a genetically-related child without a serious monogenic disease. The Commission's work focused on the clinical pathway elements on the right side.
From page 13...
... ; •  lack additional variants introduced by the editing process at off-target sites -- that is, the total number of new genomic variants should not differ significantly from that found in comparable unedited embryos; •  lack evidence of mosaicism introduced by the editing process; •  of suitable clinical grade to establish a pregnancy; and are •  have aneuploidy rates no higher than expected based on standard assisted reproductive technology procedures. Recommendation 6: Any proposal for initial clinical use of heri table human genome editing should meet the criteria for preclinical evidence set forth in Recommendation 5.
From page 14...
... However, the use of such in vitro–derived gam etes in reproductive medicine raises distinct medical, ethical, and societal issues that must be carefully evaluated, and such gametes without genome editing would need to be approved for use in a ­ ssisted reproductive technology before they could be considered for clinical use of heritable human genome editing. ESSENTIAL ELEMENTS OF OVERSIGHT SYSTEMS FOR HERITABLE HUMAN GENOME EDITING From a scientific perspective on safety and efficacy, considerations for any clinical use of HHGE should proceed incrementally.
From page 15...
... Recommendation 8: Any country in which the clinical use of heri table human genome editing (HHGE) is being considered should have mechanisms and competent regulatory bodies to ensure that all of the following conditions are met: •  individuals conducting HHGE-related activities, and their oversight bodies, adhere to established principles of human rights, bioethics, and global governance; •  clinical pathway for HHGE incorporates best practices the from related technologies such as mitochondrial replacement techniques, preimplantation genetic testing, and somatic ­genome editing; •  decision making is informed by findings from independent international assessments of progress in scientific research and the safety and efficacy of HHGE, which indicate that the technologies are advanced to a point that they could be considered for clinical use; •  prospective review of the science and ethics of any applica tion to use HHGE is diligently performed by an appropri ate body or process, with decisions made on a case-by-case basis; •  notice of proposed applications of HHGE being considered is provided by an appropriate body; •  details of approved applications (including genetic condi tion, laboratory procedures, laboratory or clinic where this will be done, and national bodies providing oversight)
From page 16...
... should be established with clear roles and responsibilities before any clinical use of heritable human genome editing (HHGE)
From page 17...
... A credible process would need to assess whether it is feasible to envision new translational pathways and ­ what they should entail, and such a body would need not only experts in science, medicine, and ethics but also representatives from the many additional stakeholder communities that could be affected by future uses of HHGE. Recommendation 10: In order to proceed with applications of heritable human genome editing (HHGE)
From page 18...
... Recommendation 11: An international mechanism should be estab lished by which concerns about research or conduct of heritable human genome editing that deviates from established guidelines or recommended standards can be received, transmitted to relevant national authorities, and publicly disclosed.


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