Jonathan Yen, PhD, on Continuing Research With Prime Editing for Sickle Cell Disease

“[Prime editing] has a lot complexity, a lot of optimizations that we have to do. And we are only reaching about 40% editing in the cells, ideally, we want to go even higher. But there is another complication, on the manufacturing side, the guide RNA is little longer, because we actually include the template. And this tag RNA as we call it, it's much longer, so the manufacturing of it is actually much harder to get good material out of it and sourcing that material. I think technology has a lot of catching up to do."

Preclinical data on prime editing in mouse models of sickle cell disease (SCD) have demonstrated a reduction of red blood cell sickling in a proof-of-concept study supporting nonviral prime editing as a treatment mode in SCD. The research was completed by researchers from St. Jude Children’s Research Hospital and the Broad Institute, in which hematopoietic stem and progenitor cells (HSPCs) were transplanted from patients with SCD into immunodeficient mice after prime editing. The researchers found that the SCD allele (HBBS) was corrected to wild type (HBBA) at frequencies of 15 to 41%. The research also showed minimal off-target editing.

CGTLive spoke to Jonathan Yen, PhD, an author on the study and the director of therapeutic genome engineering at St. Jude’s, to learn more about the challenges with prime editing and facets of the technology for which research remains to be done, including understanding the safety profile and achieving higher levels of editing in HSPCs.

REFERENCE

Everette KA, Newby GA, Levine RM, et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01026-0