Weekly reads: clonal expansion, Golden Retriever cancer, FTC hits genetics firm on testi-phony-als

Let’s start this week’s digest with a discussion of clonal expansion and mutations during cell and gene therapy development. Here’s the article that brought this to mind.

Sickle cell gene therapy process may cause cancer-linked mutations in blood stem cells, Fierce Biotech.

Clonal expansion

This is a story about a non-CRISPR gene therapy using a short hairpin RNA. Here is the source Nature Medicine paper: Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.

Clonal selection and clonal expansion refer to some cells having an evolutionary advantage over their cellular compatriots. As a result, these “fitter” cells, at least in the sense of survival and proliferation, outgrow other cells. These cellular clones may be millions or billions of times overrepresented in the population compared to neighbors.

This kind of selection of the fittest is needed for normal development such as during maturation of the immune system.

Clonal expansion gone wrong

Clonal expansion can also occur in not-so-helpful or even ultimately deadly ways. For example, as we age clones of lymphocytes can emerge and be overrepresented within our blood in a way that may predispose us to cancer. Such blood cell clones are somewhat more likely to go on to spark leukemia or lymphoma. Such adult clonal hematopoiesis can be due to accumulation of mutations and epigenetic changes.

Clonal expansion has also been reported in the skin. There too it may predispose to disease.

Here’s a nice recent review of clonal expansion in non-cancer tissues.

What does this mean for gene therapy and gene editing development?

For combination gene and cell therapies involving the immune system, there is evidence that during the processing stages needed to expand cells to make a treatment, clonal expansion may occur in ways that pose risks.

In the sickle cell trial context above, the cells ended up acquiring mutations too. These mutations did not appear to be related to the short hairpin RNA used in the lab, but their presence is a concern anyway. Some of the mutations were in genes related to cancer.

Note that I have not heard of any similar reports related to the distinct work developing CRISPR for sickle cell disease. In theory, though, any time cells are modified and expanded, clonal expansion could occur in ways that elevate risks.

Other recommended reads

• What golden retrievers are teaching us about cancer, WaPo. The story includes work and quotes from some of my UC Davis colleagues.  Here’s the original research article which finds one gene linked to both longevity and cancer in Golden Retrievers. 
• FTC and California allege CRI Genetics made deceptive DNA accuracy claims, falsified reviews, and used deceptive dark patterns, FTC. Some of the central allegations of this FTC action bring to mind the ways some stem cell clinics act too. For example, clinics often make unsupported claims. Many clinics pay other sites to recommend them as if those other websites were totally independent. Clinics also make up endorsements. It’s interesting to see the FTC using this term testi-phony-als. 
• Pregnancy-responsive pools of adult neural stem cells for transient neurogenesis in mothers, Science.