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

Abstract

Human 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.

Human germline editing: Legal-ethical guidelines for South Africa

“…However, these terms, broadly understood, can overlap. With 'research' we refer to the production of generalisable knowledge about human germline editing through systematic investigation, including preclinical studies (such as in vitro human studies and animal trials) 13 and clinical trials. With 'clinical application' we refer to the use of modified germ cells in human reproduction.…”

“…In the event that the research reaches a point, after properly designed preclinical studies, 13 where it is ready for human clinical trials -for an embryo with an edited genome to be transferred in utero for reproductive purposes -section 71 of the NHA will apply. Although editing takes place on a germ cell prior to the prospective child's existence, the research does not stop with that act, but continues through the gestation and into the child's life.…”

“…Following properly designed preclinical studies, 13 new human germline editing clinical applications should be subjected to clinical trials on humans -the same as with new medicines or medical devices. Clinical trial protocols would need to be designed mindful of the fact that germline editing is designed to be heritable.…”

Genome Editing in Translational Medicine: An Inventory

“…One of the major issues regarding the use of genome editing in clinical applications is of regulatory nature. Currently, there seem to be no clearly set standards regarding the evaluation of safety in preclinical animal models [174,175]. On the other hand, providing data about safety in a preclinical animal model can take years [176], precluding fast verification on an organismal level.…”

Future of global regulation of human genome editing: a South African perspective on the WHO Draft Governance Framework on Human Genome Editing

“…The risk, however, is that of some countries setting the bar of safety lower than is reasonably justifiable. Thus, the final Framework must speak to the questions that arise in determining the safety of germline interventions, and provide guidance on issues of global significance such as how preclinical research and clinical trials for heritable gene editing should be conducted, 8 and the viability of intergenerational monitoring. 9 The challenges in determining global benchmarks for safety and efficacy speak to a deeper challenge, which is central to the establishment of a global framework that merits further examination.…”