scholarly journals Clinical trials of germline gene editing: The exploitation problem

Bioethics ◽  
2021 ◽  
Author(s):  
Erik Malmqvist
Keyword(s):  
Clinical Trials ◽  
Gene Editing ◽  
Germline Gene

scholarly journals Intergenerational monitoring in clinical trials of germline gene editing

2019 ◽  
Vol 46 (3) ◽  
pp. 183-187 ◽  
Author(s):  
Bryan Cwik
Keyword(s):  
Clinical Trials ◽  
Gene Editing ◽  
Ethical Issues ◽  
Human Subjects ◽  
Germline Gene ◽  
Ethical Challenges ◽  
Human Subjects Research ◽  
Follow Up Study

Design of clinical trials for germline gene editing stretches current accepted standards for human subjects research. Among the challenges involved is a set of issues concerning intergenerational monitoring—long-term follow-up study of subjects and their descendants. Because changes made at the germline would be heritable, germline gene editing could have adverse effects on individuals’ health that can be passed on to future generations. Determining whether germline gene editing is safe and effective for clinical use thus may require intergenerational monitoring. The aim of this paper is to identify and argue for the significance of a set of ethical issues raised by intergenerational monitoring in future clinical trials of germline gene editing. Though long-term, multigenerational follow-up study of this kind is not without precedent, intergenerational monitoring in this context raises unique ethical challenges, challenges that go beyond existing protocols and standards for human subjects research. These challenges will need to be addressed if clinical trials of germline gene editing are ever pursued.

scholarly journals Designing Preclinical Studies in Germline Gene Editing: Scientific and Ethical Aspects

2019 ◽  
Vol 16 (4) ◽  
pp. 559-570 ◽  
Author(s):  
Anders Nordgren
Keyword(s):  
Clinical Trials ◽  
Experimental Design ◽  
Animal Studies ◽  
Gene Editing ◽  
Preclinical Studies ◽  
Germline Gene ◽  
Ethical Aspects ◽  
Human Germline Gene Editing ◽  
First Time ◽  
Modest Level

AbstractHuman germline gene editing is often debated in hypothetical terms: if it were safe and efficient, on what further conditions would it then be ethically acceptable? This paper takes another course. The key question is: how can scientists reduce uncertainty about safety and efficiency to a level that may justify initiation of first-time clinical trials? The only way to proceed is by well-designed preclinical studies. However, what kinds of investigation should preclinical studies include and what specific conditions should they satisfy in order to be considered well-designed? It is argued that multispecies and multigenerational animal studies are needed as well as human embryo editing without implantation. In order to be possible to translate to first-time clinical trials, animal studies need to satisfy strict conditions of validity. Moreover, embryo studies intended for translation to first-time clinical trials need to correspond to the animal studies in experimental design (with exception of implantation). Only in this way can uncertainty about risk for harm (safety) and prospect of benefit (efficiency) in first-time clinical trials be reduced to a modest level. If uncertainty is not reduced to such a level, first-time clinical trials in germline gene editing should not be initiated.

Ethical issues raised by intergenerational monitoring in clinical trials of germline gene modification

2020 ◽  
pp. medethics-2020-106095
Author(s):  
Austen Yeager
Keyword(s):  
Clinical Trials ◽  
Trial Design ◽  
Gene Editing ◽  
Ethical Issues ◽  
Clinical Trial Design ◽  
Careful Consideration ◽  
Future Generations ◽  
Germline Gene ◽  
Gene Modification

As research involving gene editing continues to advance, we are headed in the direction of being able to modify the human germline. Should we reach a point where an argument can be made that the benefits of preventing unborn children and future generations from inheriting genetic conditions that cause tremendous suffering outweigh the risks associated with altering the human germline, the next step will be to design clinical trials using this technology in humans. These clinical trials will likely require careful follow-up and monitoring of future generations born with altered genes. This paper addresses some of the ethical issues raised by intergenerational monitoring and sets out to show that these issues can be avoided with careful consideration and clinical trial design.

scholarly journals Human Genetic Diversity Alters Therapeutic Gene Editing Off-Target Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3993-3993
Author(s):  
Linda Yingqi Lin ◽  
Samuele Cancellieri ◽  
Jing Zeng ◽  
Francesco Masillo ◽  
My Anh Nguyen ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Clinical Trials ◽  
Genome Editing ◽  
Gene Editing ◽  
Conflicts Of Interest ◽  
African Ancestry ◽  
Great Promise ◽  
Personal Genome ◽  
Hematopoietic Stem ◽  
The Impact

Abstract CRISPR gene editing holds great promise to modify somatic genomes to ameliorate disease. In silico prediction of homologous sites coupled with biochemical evaluation of possible genomic off-targets may predict genotoxicity risk of individual gene editing reagents. However, standard computational and biochemical methods focus on reference genomes and do not consider the impact of genetic diversity on off-target potential. Here we developed a web application called CRISPRme that explicitly and efficiently integrates human genetic variant datasets with orthogonal genomic annotations to predict and prioritize off-target sites at scale. The method considers both single-nucleotide variants (SNVs) and indels, accounts for bona fide haplotypes, accepts spacer:protospacer mismatches and bulges, and is suitable for personal genome analyses. We tested the tool with a guide RNA (gRNA) targeting the BCL11A erythroid enhancer that has shown therapeutic promise in clinical trials for sickle cell disease (SCD) and β-thalassemia (Frangoul et al. NEJM 2021). We find that the top predicted off-target site is produced by a non-reference allele common in African-ancestry populations (rs114518452, minor allele frequency (MAF) = 4.5%) that introduces a protospacer adjacent motif (PAM) for SpCas9. We validate that SpCas9 generates indels (~9.6% frequency) and chr2 pericentric inversions in a strictly allele-specific manner in edited CD34+ hematopoietic stem/progenitor cells (HSPCs), although a high-fidelity Cas9 variant mitigates this off-target. This report illustrates how population and private genetic variants should be considered as modifiers of genome editing outcomes. We expect that variant-aware off-target assessment will be required for therapeutic genome editing efforts going forward, including both ongoing and future clinical trials, and we provide a powerful approach for comprehensive off-target prediction. CRISPRme is available at crisprme.di.univr.it. Disclosures No relevant conflicts of interest to declare.

scholarly journals NIH supports call for moratorium on clinical uses of germline gene editing

Nature ◽  
2019 ◽  
Vol 567 (7747) ◽  
pp. 175-175 ◽  
Author(s):  
Carrie D. Wolinetz ◽  
Francis S. Collins
Keyword(s):  
Gene Editing ◽  
Germline Gene

scholarly journals Germline gene editing and the precautionary principle

Bioethics ◽  
2019 ◽  
Vol 34 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Julian J. Koplin ◽  
Christopher Gyngell ◽  
Julian Savulescu
Keyword(s):  
Precautionary Principle ◽  
Gene Editing ◽  
Germline Gene ◽  
The Precautionary Principle

scholarly journals Targeted delivery of CRISPR-Cas9 ribonucleoprotein into arthropod ovaries for heritable germline gene editing

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Duverney Chaverra-Rodriguez ◽  
Vanessa M. Macias ◽  
Grant L. Hughes ◽  
Sujit Pujhari ◽  
Yasutsugu Suzuki ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Gene Editing ◽  
Germline Gene
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