CTA: What are some of the social and ethical concerns about the medical use of gene editing? Are there concerns particular to genome editing’s potential applications in oncology?

Dr Carroll: Let’s divide this into somatic therapies and germline genome editing. The 3 principal concerns with the former are efficacy, safety, and distribution. We wouldn’t want to apply procedures that had little or no effect, or that caused more problems than they cured.

It is safe to say that near-term applications of expensive genome editing therapies will be confined to relatively wealthy populations and individuals. From a social and ethical perspective, this is an important concern.

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We might also consider that there are at least 2 brands of somatic therapy – ex vivo and in vivo. The former allows convenient methods of delivery of the editing reagents and a lot of characterization of the edited products, while we have less control over the latter, and delivery presents significant challenges in many cases.

In addition to those issues, germline modifications raise the concern that the recipient of the modification and all of his/her descendants will be affected. Thus, if something other than the desired edit is made, there is no going back. As the capability for doing germline editing develops, there will be tensions among the desires of families that carry disease alleles, natural cautions surrounding a novel technology, and the sense that humans will be “playing God” by taking such a radical step.

CTA: Are expectations outstripping the likely capabilities of genome editing technology? What are some of the challenges or limitations for clinical gene repair applications?

Dr Carroll: I would say we are still largely in the technology-development stage of genome editing, particularly as it applies to clinical applications. At present, the most significant challenges are improving the efficiency of homology-dependent repair and delivery of the required components. To correct a defective allele, whether ex vivo or in vivo, we need to have cells use a DNA template that we provide to repair the nuclease-induced targeted DNA break, such as reversion of the sickle cell mutation. This type of repair is inefficient, particularly in primary cells.

When cells are treated ex vivo prior to introduction to a patient, we have quite a number of options for delivering the editing materials. In cases where in vivo delivery is envisioned, the options are more limited. Taking lessons from many years of gene therapy research, people are using viral vectors and methods of enhanced DNA delivery to overcome this limitation.

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