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3 Potential Applications of Heritable Human Genome Editing
Pages 95-120

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From page 95...
... It then sets out the Commission's conclusions about the circumstances in which a translational pathway could responsibly be described for HHGE and explains why it is not possible at present to describe a responsible translational pathway for other types of potential use. DEFINING APPROPRIATE USES OF HERITABLE HUMAN GENOME EDITING Decisions about the clinical use of HHGE involve issues that are complex and arguably unprecedented, because the potential range of modifications that could be made to the human genome is vast (from correcting a known disease-causing mutation to inserting new genes or regulatory 95
From page 96...
... The second issue is at the heart of the Commission's task: defining responsible translational pathways for particular uses of HHGE, should a country judge the uses appropriate. Defining responsible translational pathways clearly involves scientific considerations, but it also entails s ­ocietal and ethical considerations related to weighing potential benefits and harms, and uncertainties about them, in the clinical evaluation of a new medical technology.
From page 97...
... CRITERIA FOR DEFINING RESPONSIBLE TRANSLATIONAL PATHWAYS FOR INITIAL USES OF HERITABLE HUMAN GENOME EDITING A number of considerations are common to the initial human use of new biomedical technologies: the prioritization of safety, very careful selec­ tion of a small number of initial cases, emphasis on a favorable balance of risks and potential benefits, and careful review of initial results prior to additional uses. New interventions, with necessarily high degrees of uncertainty about their efficacy, tend to focus on diseases and individuals for whom there are no available alternatives, and on diseases or conditions for which mortality is high and/or morbidity is severe, thereby reflecting the most favorable balance of potential harms and benefits.
From page 98...
... In order to create the most favorable balance of potential harms and benefits, new interventions with substantial uncertainties ideally focus on diseases and prospective parents for whom there are no available alternatives, and on diseases or conditions for which mortality is high and/or morbidity is severe. The use of seriousness of a condition as a criterion for medical intervention is common in laws, regulations, and policy statements (Kleiderman et al., 2019; Wertz and Knoppers, 2002)
From page 99...
... To maximize potential benefit and minimize potential harm, it would be appropriate to confine initial uses to prospective parents who lack viable options. CRITERIA FOR POSSIBLE INITIAL USES OF HERITABLE HUMAN GENOME EDITING Based on the above principles, the Commission identified four criteria that should be met by any proposed initial uses of HHGE, in the event
From page 100...
... have no option for having a genetically-related child that does not have the serious monogenic disease, because none of their embryos would be genetically unaffected in the absence of genome editing; or (ii) have extremely poor options, because the expected proportion of unaffected embryos would be unusually low, which the Commission defines as 25 percent or less, and have attempted at least one cycle of PGT without success.
From page 101...
... • Autosomal recessive disease. If both parents carry two disease-­ causing alleles in the same gene (affected homozygotes)
From page 102...
... First, for couples in this category prenatal diagnosis and PGT, which can identify fetuses and embryos that have not inherited the disease-causing genotype, have no chance of identifying genetically unaffected embryos. Second, the embryos exposed to risks associated with genome editing procedures would be only those carrying the disease-causing genotype for a serious monogenic disease.
From page 103...
... . Only some of these instances fall into Category B, because some monogenic diseases do not meet the Commission's definition of being serious for the purpose of defining a responsible translational pathway for HHGE, and some couples have affected children due not to inherited mutations but to newly arising (de novo)
From page 104...
... Category B would therefore involve subjecting all embryos to risks associated with genome-editing procedures -- including those that do not have the disease genotype and thus do not require genome editing. Possible alternative approaches for the application of HHGE that would avoid editing unaffected embryos are discussed below.
From page 105...
... When only one parent is a carrier, the case would belong in Category C, since only heterozygous or unaffected embryos could result. A second group of examples involves genotypes that may affect an individual's quality of life but are not serious monogenic diseases within the meaning of the Commission's definition (a disease that causes severe morbidity or premature death)
From page 106...
... Rather, it involves genetic changes directed toward other objectives, which may or may not be health-related and may involve introducing genetic sequences that do not naturally, or only very rarely, occur in the human population.
From page 107...
... For example, constitutive activation of the EPO gene has been proposed to confer advantages in endurance sports (Brzeziańska et al., 2014) ; • attempting to modify traits such as height or cognitive ability that are influenced by hundreds or thousands of genetic variants across the genome; and • attempting to confer new abilities, not found in humans, by adding sets of genes that, for instance, might confer resistance to radiation exposures encountered during extended spaceflight.
From page 108...
... Category A Category A clearly meets the four criteria for initial uses of HHGE: (1) The category involves serious monogenic diseases.
From page 109...
... of PGT cycles in which at least one embryo reaches the diagnosis stage results in an unaffected embryo that can be transferred to the uterus. The primary interest in HHGE in Category B is to assist couples who have very low prospects of having an unaffected child, owing to few unaffected embryos being available for transfer.
From page 110...
... for whom the expected proportion of unaffected offspring is 25 percent or less (for ­ example, couples in which both parents are heterozygous for the same or different dominant serious monogenic diseases)
From page 111...
... HOW COMMON ARE THE CIRCUMSTANCES FOR THE INITIAL CLINICAL USES OF HERITABLE HUMAN GENOME EDITING? The Commission next considered the frequency of the circumstances for initial uses of HHGE defined above, to determine whether there is likely to be an adequate number of suitable couples to enable initial studies to evaluate efficacy and safety, which we judge to be approximately 10–20 couples.
From page 112...
... As noted above, Category A arises only for the minority of serious monogenic diseases that are compatible with individuals surviving to reproductive age and being able to reproduce. Examples of diseases where this is the case are Huntington's disease, CF, sickle cell anemia, and beta-thalassemia.
From page 113...
... is often in the range of 4.5 × 10–3 for a serious autosomal recessive disease and 2 × 10–5 for a serious autosomal dominant disease.7 From these values, the expected frequency of couples in Category A occurring by chance for a particular gene would be expected to be in the range of 4 × 10–10 for a recessive disease and 8 × 10–10 for a dominant disease -- that is, in the range of 4–8 per 10 billion for any given disease gene. If there were 100 similar genes in this category, the total frequency of couples in Category A would be about 100-fold higher (about 4–8 per 100 million couples)
From page 114...
... restricts initial uses of HHGE to producing naturally occurring alleles that ­ are common in the relevant population. The examples of Huntington's and sickle cell anemia demonstrate that even among serious monogenic diseases where affected individuals survive to an age when they could have children, there are genetic and environmental factors that complicate the analysis of potential harms and benefits arising from HHGE.
From page 115...
... that there may be many couples with both members homozygous for beta-thalassemia. Sickle Cell Disease in Sub-Saharan Africa and the United States SCD is an autosomal recessive disorder occurring when an affected individual carries two copies of the allele for sickle cell trait.
From page 116...
... To fit the circumstances of the very small subset of Category B, both prospective parents would need to be heterozygous for the same or different serious dominant disease(s)
From page 117...
... s Mutations in the gene APC cause the disease familial adenomatous polyposis, which results in the development of colon cancer by middle age as well as increased risk of cancer in other organs. Familial adenomatous polyposis has been reported to occur in 1 in 7,000 to 1 in 22,000 people.13 Although both parents would need to carry alleles for a serious dominant disease to meet the circumstances identified by the Commission for potential initial uses of HHGE, it may not be necessary for parents to carry alleles for the same disease.
From page 118...
... Such studies will lead to better understanding of the reasons for the limited success of IVF for some prospective parents and may well help our understanding of female infertility and miscarriage. Research using genome editing in human embryos will also give important insight into the effects of maternal aging on human embryo development, an area of increasing interest with a growing
From page 119...
... For all other circumstances, additional considerations and lack of knowledge make it impossible today to properly evaluate the balance of risks and benefits, and the Commission is not currently able to describe a responsible translational pathway for clinical use.
From page 120...
...  use of HHGE is limited to serious monogenic diseases; the the Commission defines a serious monogenic disease as one that causes severe morbidity or premature death; 2.  use of HHGE is limited to changing a pathogenic ­ enetic the g variant known to be responsible for the serious monogenic disease to a sequence that is common in the relevant popu lation and that is known not to be disease-causing; 3.


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