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Heritable Human Genome Editing (2020) / Chapter Skim
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4 A Translational Pathway to Limited and Controlled Clinical Applications of Heritable Human Genome Editing
Pages 121-144

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From page 121...
... prospective parents for whom all children would inherit the disease-causing genotype for a serious monogenic disease and who therefore have no alternative for having genetically-related offspring unaffected by the disease (Category A)
From page 122...
... In this report, the Commission identified the elements that could form a translational pathway for cases of serious monogenic diseases in which all or a significant majority of the prospective parents' children would inherit the disease-causing genotype. The specific use of HHGE proposed for this pathway must therefore be one that falls within these categories of circumstances.
From page 123...
... BOX 4-1 Essential Elements of a Responsible Translational Pathway Toward Initial Clinical Uses of HHGE Basic Research Foundation: Undertake continued basic research to optimize genome editing technologies Preclinical Evidence to Support a Proposed Use: Develop a proposed meth odology for a specific use and obtain preclinical evidence • Need for extensive research in cultured human cells and in zygotes of model organisms ° Assessment of parental genomes ° Testing of genome editing reagents in cultured parental cells ° Testing of genome editing reagents in embryos of model organisms • Preclinical testing in human embryos ° Characterization of editing at the target site ° Characterization of any off-target editing ° Characterization of any mosaicism ° Characterization of embryo development Decision Points and Required Approvals: Obtain all required approvals, includ ing those specified by national regulatory systems, and obtain informed parental consent Undertake Clinical Evaluation of a Proposed Use • Create genome-edited human embryos intended for transfer to establish a pregnancy • Characterize human embryos intended for transfer Evaluate Clinical Outcomes • Monitor a resulting pregnancy • Undertake longer-term monitoring and follow-up of any child born following HHGE • Make information on decisions to permit the clinical evaluation of HHGE publicly available • Evaluate information to inform future decisions about HHGE
From page 124...
... As emphasized in Chapter 3, the proposed clinical use also needs to be one that would fall within the set of circumstances for which the Commission was able to describe a translational pathway given the current state of scientific and clinical knowledge. For any initial uses, HHGE would represent a new technological intervention in the assisted reproductive technology (ART)
From page 125...
... if introducing a double-strand break is part of the methodology; and characterizing processes in human embryos that influence editing outcomes and may differ from those in somatic and ­ cultured cells. Accumulating evidence will help to decide to what extent cultured cells, model organisms, or other surrogates can be used to confidently predict events in human zygotes.
From page 126...
... If genome editing continues beyond the first cell division, different cells in an embryo may carry different sequence changes at the intended target or at off-target sites. The effect of such mosaicism is difficult to predict, but it may pose serious risks by either failing to prevent disease due to target tissues having an insufficient number of appropriately edited cells or by introducing undesired mutations -- particularly large copy number variants -- at the target locus or elsewhere in a fraction of cells that could result in diseases related or unrelated to the targeted disease.
From page 127...
... For any specific clinical use, the particular reagents and processes will need to be tested carefully at the particular genomic site and in the particular context as far as possible, as described below. Sufficient Preclinical Evidence to Support Clinical Evaluation of the Proposed Use To undertake HHGE through the use of zygotes, the genome-editing reagents would most likely be injected directly into oocytes concomitant with sperm or into zygotes immediately after fertilization.
From page 128...
... To justify the design of the editing reagents proposed for potential clinical use, preclinical research in cultured human somatic cells from the prospective parents and in model organisms must include the following steps. Assessment of Parental Genomes Requirement: Obtain whole-genome sequences of the prospective parents using best practice protocols for investigating genetic disorders.
From page 129...
... Since some embryo-specific characteristics are likely shared among species, testing the editing reagents in zygotes of mammalian model organisms allows the characterization of the types of edit­ng outcomes and the development of procedures to prevent and i 1  See https://www.ddduk.org/intro.html. The Deciphering Developmental Disorders study is funded by the Health Innovation Challenge Fund and the Wellcome Sanger Institute to analyze genomic information from "over 12,000 undiagnosed children and adults in the U.K.
From page 130...
... If the humanized sequence cannot be produced in a mammalian model organism for some reason, then this disease allele should not be selected for an initial application of HHGE. Preclinical Testing in Human Embryos Preclinical testing in human zygotes must be undertaken to demonstrate that the genome-editing methodology proposed for clinical use provides high levels of efficiency, specificity, and safety.
From page 131...
... In such circumstances, it might become acceptable to use these cells as a surrogate for the preclinical tests involving human embryos required in this pathway. Rigorous scientific assessment of such models and their ability to substitute for evaluation in human embryos would be critical before using such alternative cell systems as the only source of preclinical evidence for HHGE.
From page 132...
... Identifying off-target sites from analysis of the cultured parental cells (see the first step under "Need for Extensive Research in Cultured Human Cells and in Zygotes of Model Organisms," above) would provide an initial indication of high-risk off-target sites in the embryo, allowing attention at this stage to focus on regions where off-target editing has previously been observed or might be anticipated to occur.
From page 133...
... Examples of best practice protocols include those used by the Newcastle ­ Fertility Centre at the International Life Science Centre and others in the preclinical evaluation of human embryos that had undergone mitochondrial replacement techniques (MRT)
From page 134...
... Determination That Heritable Human Genome Editing Could Be Considered for Clinical Use in a Country As described in Chapter 1, a country must first allow the consideration of HHGE for the proposed clinical use. This decision making will not only include information on preclinical evidence of an appropriate genomeediting methodology, but also include societal engagement and input.
From page 135...
... CLINICAL EVALUATION OF THE PROPOSED USE Once all of the required preclinical evidence had been assembled, indicating that a suitable methodology was available, and all of the appropriate regulatory reviews and approvals had been completed, a genome-edited human embryo might be generated with the aim of establishing a pregnancy. The required clinical elements include the following.
From page 136...
... Characterize Human Embryos Intended for Transfer Requirement: Perform an embryo biopsy to collect cells from the trophectoderm of blastocyst-stage embryos and perform PGT to confirm the presence of the precise on-target edits, the absence of detectable off-target mutations, and no evidence of mosaicism. Context: As detailed above, extensive preclinical evidence must demonstrate that a methodology is consistently able to deliver human embryos in which every cell has the appropriate genetic features following genome editing.
From page 137...
... Monitor a Resulting Pregnancy Requirement: Careful monitoring of a resulting pregnancy with a genomeedited embryo is strongly recommended. Context: Following transfer of a genome-edited embryo to establish a pregnancy, prenatal monitoring is crucial to detect any fetal abnormalities or other issues arising during the pregnancy.
From page 138...
... In conjunction with further extensive societal engagement, such information would also contribute to any decisions about whether to consider the clinical evaluation of HHGE for other uses in Categories A and B, according to the translational pathway identified in this report, whether or how to modify any of the preclinical or clinical requirements laid out in this translational pathway, or potentially whether to consider evaluating uses that would fall into other categories of potential uses described in Chapter 3. HERITABLE HUMAN GENOME EDITING USING IN VITRO STEM CELL–DERIVED GAMETES: WHAT A POTENTIAL TRANSLATIONAL PATHWAY WOULD ENTAIL Chapter 2 describes the prospect of genome editing in human gamete ­ precursors by two approaches: editing gamete precursor cells, such as s ­ permatogonial stem cells (SSCs)
From page 139...
... Because this technology is not yet available for approval in any clinical setting, it would be premature to describe a translational pathway that uses it to create heritable genomic changes. Nevertheless, the section below describes preclinical and clinical ­ considerations that would be relevant to such a pathway were it ever to be feasible.
From page 140...
... Before any clinical use to create a human embryo for transfer to the uterus, preclinical research for genome editing approaches using in vitro stem cell–derived gametes would include the following. • Extensive research in human cells to develop and optimize the ­ enome editing reagents.
From page 141...
... The Commission's recommendations set out the components that would be required for a responsible translational pathway and are provided below. Scientific Validation and Standards for Any Proposed Use of Heritable Human Genome Editing Evidence from preclinical research would be required to establish that HHGE may be safe enough to consider evaluating in first-in-human clinical
From page 142...
... ; •  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 143...
... The ability to generate large numbers of such stem cell–derived gametes would provide a further option for p ­ rospective parents to avoid the inheritance of disease through the efficient production, testing, and selection of embryos without the disease-causing genotype. However, the use of such in vitro– derived gametes 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 assisted reproductive technology before they could be considered for clinical use of heritable human genome editing.


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