A blueprint for translating genome-editing strategies to clinical trials

Treatments for sickle cell disease, a genetic blood disorder associated with chronic anemia, severe pain crises, progressive multiorgan damage, and early mortality, have limitations because currently approved drugs, such as hydroxyurea, are only partially effective. Allogenic bone marrow transplantation is potentially curative but is associated with immune toxicities, such as graft-versus-host disease and graft rejection. Matched donors for the procedure are also limited; less than 20% of patients with sickle cell disease find a match. Genome editing of patients’ stem cells could circumvent these challenges.

Published in Molecular Therapy, St. Jude scientists detailed the safety and efficacy of a gene editing approach that induces fetal hemoglobin. Hemoglobin is a red blood cell protein that carries oxygen throughout the body. Sickle cell disease affects this protein, but fetal hemoglobin (present before birth) offers an alternative. By editing blood stem cells to express fetal hemoglobin, researchers may be able to treat sickle cell disease. 

The approach, initially developed in the lab of co-corresponding author Mitch Weiss, MD, PhD, Department of Hematology chair, uses a CRISPR-Cas9 genome editor programmed to make targeted DNA double-stranded breaks. The researchers used this editor to interfere with the target of a repressor protein called BCL11A, which ceases fetal hemoglobin expression in adult blood cells. 

“We compared different possible editing targets and identified a lead target that was not only highly effective at inducing fetal hemoglobin but also highly specific,” said co-corresponding author Shengdar Tsai, PhD, Department of Hematology. “To understand where Cas9 was acting in the edited cells’ genome, we used an approach my lab developed called CHANGE-seq; it selectively sequences DNA modified by genome editors.”

The lab of co-corresponding author Jonathan Yen, PhD, Department of Hematology, optimized the cell-editing process at the clinical scale by collaborating with the St. Jude GMP. They demonstrated they could edit cells at the quantity and quality required to treat patients in a clinical trial.

Preclinical studies showed that Cas9 editing at the targeted binding site induced fetal hemoglobin to levels predicted to be therapeutically effective with no detectable off-target effects in the edited human hematopoietic stem cells. These results prompted the team to open the first genome editing clinical trial at St. Jude, called St. Jude Autologous Genome Edited Stem Cells (SAGES-1). 

In addition to providing the foundation for future St. Jude studies, this work supplies a blueprint for other researchers. “We described the complete story of developing a genome editing strategy to treat sickle cell disease from preclinical studies to scaling up the editing process to clinical readiness and understanding of safety and potential toxicities,” said Tsai. “By publishing these studies, we hope to help other groups by providing an example of studies required to clear an investigational new drug application.”

The team anticipates this study will be the first of a series of advances in genome editing medicines at St. Jude. They hope to catalyze similar efforts both at St. Jude and elsewhere.