Chapter 117
Curing Rare Diseases — 6
That’s not the only use of genome editing to deal with the immune system. By editing multiple genes that would lead to transplant rejection, pig organ transplantation of hearts and kidneys to patients have become possible and will potentially, if proven safe and providing durable benefit, greatly alleviate the shortage of donor human organs. Clinical trials in participants with human immunodeficiency virus (HIV-1) were initiated by Excision BioTherapeutics, with CRISPR-Cas9 to cut at two sites within the HIV genome to eliminate HIV from cells, but initial results were disappointing. For type 1 autoimmune diabetes, CRISPR is being used to edit immune-related genes to prevent the pancreatic islet cell transplant, made from the individual’s stem cells, from being attacked.
Success with in vivo correction of cystic fibrosis in the experimental model has helped propel the start of clinical trials of genome editing with an mRNA and nanoparticle package for this condition. If a one-and-done editing approach works, it might simulate the very high efficacy of Trikafta therapy that requires lifetime daily dosing.
Targeting cells outside the body (ex vivo) for editing is not as difficult, which is why the first approvals have come for sickle cell disease and beta-thalassemia. And the many uses for cancer are exemplified by clinical trials of base editing a healthy person’s T cells at multiple sites and using this as an off-the-shelf treatment for T cell leukemia, a rare cancer that is difficult to treat. Engineering T cells to drive a more potent immune response against solid cancers has moved forward in clinical trials with multiple neoantigens.
Arecent outgrowth of rare disease omics is the finding that in people with Laron syndrome, a cause of dwarfism in fewer than five hundred people in the world who have a considerably lower risk of heart disease, diabetes, cancer, and other age-related diseases, their insulin-like growth factor IGF-1 levels are quite low. That substantiated the IGF-1 gene’s role in the aging process and increased the interest for a targeted drug intervention.
All of this looks encouraging but there are many hitches. It has been shown that base and prime editors can still induce double-strand DNA breaks, with potential genotoxicity of the unintended by-products, albeit at a much lower frequency. There is significant concern about off-target effects for all types of genome editors: cleavage or nicks in DNA that are unintended because the guide RNA doesn’t have perfect specificity. Fortunately, they occur less frequently with base or prime editing. But permanent edits in a person’s genome in some cells, even though they are typically small insertions or deletions, can have large consequences. When I spoke to David Liu, the inventor of base and prime editing, he nicely contextualized this issue: