LONDON The international commission convened in the aftermath of Chinese scientist He Jiankuis shock announcement of the birth of gene edited twins has set a possible course to approval of heritable gene editing, but said the technique is far from ready for use.

At this time, it is not possible to specify how to move from research to clinical application because it is not possible to make precise edits, or avoid introducing off-target effects, the committee said.

No clinical use should be considered until it is clear it can be done precisely. There are a lot of gaps at the moment, said Kay Davies, commission co-chair and professor of genetics at Oxford University, speaking at the launch of the report.

Should they ever be used, it is vitally important that these technologies are used for medically justified interventions based on rigorous understanding of how the pathogenic variant leads to disease, Davies said.

If and when heritable human genome editing is proved reliable, initial applications should be limited to the prevention of serious monogenic diseases, such as cystic fibrosis, thalassemia, sickle cell anemia and Tay-Sachs disease, but only in cases where even with in vitro fertilization and preimplantation screening of embryos, couples would have no chance of having a biologically related child that was not affected by the condition.

As the report notes, instances where both prospective parents are homozygous for a disease gene are very rare. Even for a dominant disorder that can be inherited from a single defective gene, it would be rare for one parent to be homozygous. Commission member Michele Ramsay, of the University of the Witwatersrand, South Africa, said fewer than 20 families worldwide are likely to meet the criteria.

Thats why we need international cooperation, so it is transparent and open, and data can be pooled, Ramsay said. No floodgates are going to be opened for the initial uses we recommend.

The International Commission on the Clinical Use of Human Germline Gene Editing, set up by the U.K. Royal Society and the U.S. National Academies of Science and of Medicine, involves 18 expert members from 10 countries. They spent a year reviewing the scientific literature on CRISPR and other gene editing tools, consulting peer and patients groups and meeting the public.

For the prevention of serious monogenic disease, the commission has defined a responsible clinical translation pathway, from rigorous preclinical research that determines whether and how editing can be performed efficiently and with high accuracy, to clinical application, said Richard Lifton, co-chair of the commission and president of Rockefeller University.

Key technical barriers are assessing if an edit will be corrective and demonstrating the intended edit is present in all cells. These criteria for safe and effective use have not been met yet, said commission member Haoyi Wang, of the Chinese Academy of Sciences. The report sets out the progress of research needed to show editing is effective, and [can be done] with high specificity and accurate on target charges, without causing off-target effects or mosaicism, Wang said.

No one should be attempting to follow Hes example as things stand, the commission said. All countries in which human gene editing is being researched should put in place regulation to oversee progress toward potential clinical uses, and to prevent and sanction unapproved use.

There is great concern about the potential for rogue scientists embarking on heritable gene editing on their own, Lifton said. Ultimately, regulation will be at the countrywide level, but weve got to ensure the conditions are met to ensure proper regulatory oversight. There must be a mechanism for case by case evaluation and staged rollout of the technology, he said.

More research needed

To back those national regulations, an international science advisory panel should be established to continuously follow progress, assess if preclinical requirements have been met, review data on clinical outcomes from any regulated uses of human germline editing, and advise on risks and benefits of other potential applications.

More research is needed into the technology of genome editing in human embryos, to ensure that precise changes can be made without undesired off-target effects, said Davies. International cooperation and open discussion of all aspects of genome editing will be essential.

In addition to a scientific panel to follow the science, the commission also calls for a hotline to be set up, through which researchers could raise concerns about any inappropriate use of germline editing. I would emphasize the importance of a whistleblowing mechanism, said Davies. It is suggested this could be modeled on the World Anti-Doping Agency, which polices the use of prohibited substances in sports.

The commission stresses that it was solely concerned with assessing the science and defining the specific criteria and standards required before clinical use of germline editing is considered.

A separate committee set up by the World Health Organization and co-chaired by Margaret Hamburg, former head of the U.S. FDA, is looking at ethical issues and developing governance mechanisms for both heritable and somatic gene editing. The WHO committee is expected to publish its guidance later this year.

In December 2019, He was sentenced to three years in prison and fined $430,000 for illegally carrying out the human gene editing that led to the birth of the twin girls and of another baby, with heritable changes to their genomes.

As to how far in the future approval for germline gene editing might be, Wang said the technology is moving fast. Its a bit difficult to predict, but Im quite optimistic it will become more precise. Advances also will be needed in single cell genome sequencing to ensure there are no off-target effects, he said.

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Commission urges international cooperation, continuing research in gene editing report - BioWorld Online