Human Genome Editing Science, Ethics, and Governance (2017) / Chapter Skim
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4 Somatic Genome Editing
4 Somatic Genome Editing
Pages 83-110
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From page 83... ...
, the effects of changes made to somatic cells are limited to the treated individual and would not be inherited by future generations. The idea of making genetic changes to somatic cells, referred to as gene therapy, is not new,1 and considerable progress has been made over the past several decades toward clinical applications of gene therapy to treat disease (Cox et al., 2015; Naldini, 2015)
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From page 84... ...
base pairs long, and the two inherited genomes in each somatic cell (diploid) encode the information required for the assembly and functioning of a person's cells and body throughout life.
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From page 85... ...
Whether a particular variant is advantageous or deleterious, however, can vary with the context and may be a consideration in deciding whether to edit variants for clinical benefit. Genetically Inherited Diseases One primary impetus for interest in possible clinical applications of the recent advances in genome editing is the possibility that they provide new avenues for treating and preventing human disease.
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From page 86... ...
ADVANTAGES OF GENOME EDITING OVER TRADITIONAL GENE THERAPY AND EARLIER APPROACHES Gene therapy is the introduction of exogenous genes into cells with the goal of ameliorating a disease condition. This is most efficiently done using viral vectors that take advantage of a virus's natural ability to enter cells.
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From page 87... ...
, more flexible and precise genetic modifications, such as those made possible by targeted genome editing, are needed to further improve the safety of gene therapy and broaden its application to the treatment of more diseases and conditions. Until the past decade, attempts to use genome modification in the treatment of genetically inherited disease, also called gene targeting, were made by introducing a DNA template carrying the desired sequence into a cell population in culture, and then either allowing insertion at a random location or relying on rare homologous recombination events to incorporate that template sequence at an intended location in the genome.
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From page 88... ...
Safety and Effectiveness Nuclease-based genome editing may abrogate the risk of insertional mutagenesis inherently associated with prior gene-replacement vectors that integrate quasi-randomly throughout the genome, although late-generation integrating vectors used today may mitigate this risk. In addition, in situ gene correction of inherited mutations using genome editing reconstitutes both the function and the physiological control of expression of the mutant gene.
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From page 89... ...
Indeed, one of the first potential applications of ex vivo genome editing may well be stem cell–mediated correction of primary immunodeficiencies -- an improvement over prior transgenic approaches in which ectopic or constitutive expression of the therapeutic gene posed a risk of cancerous transformation or malfunction. If on-target editing frequencies of clinically relevant cell types are high enough to be therapeutically useful, genome editing may eventually outperform gene replacement (traditional gene therapy)
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From page 90... ...
. These issues are not new, however, nor are they specific to the CRISPR-Cas9 system; many of them have already been confronted and addressed in the context of earlier gene therapy and genome-editing applications.
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From page 91... ...
are modified -- in particular, whether the modification is made in somatic cells or tissues, which do not con tribute to future generations; in a germ cell or germ cell progenitor, which can result in heritable changes passed to future children; or in a zygote, in which case both somatic and germ cells would be modified. (The focus here is on somatic editing; germline editing is discussed in Chapter 5)
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From page 92... ...
HDR Clinical development Edit to non-disease causing variant Sickle-Cell Autosomal recessive Ex vivo (HSPC) NHEJ Preclinical Induction of fetal Disease/β-Thalassemia hemoglobin Severe Combined X-linked recessive Ex vivo (HSPC)
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From page 93... ...
to milder Becker's muscular dystrophy Huntington's Disease Autosomal In vivo NHEJ Discovery Delete disease-causing dominant expanded triplet repeat Neurodegenerative Various Ex vivo HDR Conceptual Engineer cells to secrete Diseases or neuroprotective factors in vivo * Current information on clinical trials is available at ClinicalTrials.gov.
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From page 94... ...
. Several potential applications of genome editing entail causing gene disruption, provided that the delivery of the nuclease does not lead to loss of the treated cells because of toxicity or immune rejection.
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From page 95... ...
In ex vivo editing, it is possible to conduct a number of checks on the edited cells before they are administered to a patient because the cells are first manipulated in the laboratory. Ex vivo editing, which occurs outside the body, is suitable only for certain cell types, however.
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From page 96... ...
Several somatic cell types have been isolated, genetically modified, and transplanted, including blood-forming hematopoietic (blood) stem and progenitor cells, fibroblasts, keratinocytes (skin stem cells)
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From page 97... ...
Currently this process has been established for only a few cell types, including cells that will eventually give rise to skin, bone, muscle, blood, and neurons. The range of possible ex vivo genome-editing applications will expand with the development of scientific knowledge about how to isolate additional primary cell types and derive other cell types from pluripotent cells, grow the cells ex vivo, and ultimately transplant them back into patients successfully and safely.
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From page 98... ...
modification of the germ cells or primordial germ cells; therefore, preclinical development of in vivo editing should address the risk of modification of germ cells resulting in heritable changes that could be passed on to future generations and minimize this potential risk in humans enrolled in clinical trials. In general, the risk of germline transmission associated with the administration of ex vivo genome-edited cells is likely to be low if one can show that the editing reagents do not remain associated with the treated cells and are not shed in active form at the time of administration.
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From page 99... ...
for patients undergoing in vivo gene therapy in clinical trials, at least for the expected time of clearance of the administered vector/vehicle from the body fluids, and usually extended to encompass at least one cycle of spermatogenesis (approximately 64-74 days in men)
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From page 100... ...
. Most recently, it was reported that one of these methods, homology-independent targeted gene integration, or HITI, allows targeted knock-in of DNA sequences in dividing cells (e.g., stem cells)
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From page 101... ...
The innate responses to viruses may vary with virus and cell type: usually they are very low for AAV or lentivirus in human somatic cells (Kajaste-Rudnitski and Naldini, 2015) , with the exception of some immune cell types, such as dendritic cells and macrophages, which have a large complement of built-in viral sensors and may trigger interferon and inflammatory responses (Rossetti et al., 2012)
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From page 102... ...
Ongoing work in standard gene therapy, for example, has indicated that uncontrolled lentiviral insertions, which cause even more disruptive changes than nonhomologous repair of a double-strand break, may be relatively safe and well tolerated in several types of cells and tissues. This is true even when large numbers of insertions
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From page 103... ...
ETHICAL AND REGULATORY ISSUES POSED BY SOMATIC CELL GENOME EDITING In most respects, somatic cell genome editing will be developed with the benefit of gene therapy's robust base of technical knowledge, and within the existing system of regulatory oversight and ethical norms that have facilitated the current research and clinical development of somatic cell and gene therapy around the world, including the Australia, China, Europe, Japan, and the United States (see Chapter 2)
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From page 104... ...
But when long-term risks are present, "a gene therapy clinical trial must provide for long-term follow-up observations in order to mitigate those risks" (FDA, 2006, p.
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From page 105... ...
because the specificity of edited cells makes such applications less likely at this time. Several technical challenges faced in moving somatic genome editing toward clinical testing have already been met by conventional somatic gene therapy.
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From page 106... ...
Like traditional gene therapy, somatic genome editing could be used to revert an underlying genetic mutation to a variant not associated with disease, which would result in a fraction of the targeted cells regaining normal function. Somatic genome editing also could be used to engineer a cell so that its phenotype differed from that of a normal cell and was better able to resist or prevent disease.
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From page 107... ...
Although human genome editing may be somewhat more difficult to control than traditional gene therapy because technical advances have made the editing steps easier to perform, the cellular manipulations and delivery of edited cells to the patient continue to demand high-quality laboratory and medical facilities, which generally will ensure that regulatory oversight is in place. Preventing Premature or Unproven Uses of Genome Editing The issue of unregulated therapy has been particularly problematic in the field of stem cell/regenerative medicine, with rogue entities around the world making scientifically unfounded claims about stem cell therapies and profiting from desperate patients (Enserink, 2016; FDA, 2016b; Turner and Knoepfler, 2016)
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From page 108... ...
And an International Fetal Transplantation and Immunology Society has been formed, which holds annual meetings to review prospects and progress for fetal gene therapy.10 Although fetal genome editing has potential advantages, at least two special ethical issues would need to be addressed: special rules for consent (see Chapter 2) and the increased risk of causing heritable changes to the germline by causing modification of germ cells or germ cell progenitor/ stem cells.
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From page 109... ...
. Human genome editing in somatic cells holds great promise for treating or preventing many diseases and for improving the safety, effectiveness, and efficiency of existing gene therapy techniques now in use or in clinical trials.
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From page 110... ...
RECOMMENDATION 4-3. Oversight authorities should evaluate the safety and efficacy of proposed human somatic cell genome editing applications in the context of the risks and benefits of intended use, recognizing that off-target events may vary with the platform technology, cell type, target genomic location, and other factors.
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