Novel gene therapy trial for sickle cell disease launches in the US

Novel gene therapy trial for sickle cell disease launches in the US

The study uses CRISPR to correct sickle cell mutation and aims to free patients of the disease.
UCSF Benioff Children’s Hospital Oakland is enrolling patients in an innovative clinical trial that seeks to cure sickle cell disease. The trial is the first in the U.S. to apply non-viral CRISPR-Cas9 gene-editing technology in humans to directly correct the genetic mutation that causes the disease (1). The research involves taking the patient’s blood stem cells to correct the mutation and returning those edited cells to the patient through a bone marrow transplant. It’s hoped the corrected blood stem cells will then multiply and create a new blood system, one free of sickle cell. “This therapy is intended to eliminate sickle cell disease by applying CRISPR technology that is safer than a standard stem cell transplant from a healthy bone marrow donor,” Mark Walters, MD, a professor of pediatrics at UCSF and principal investigator of the clinical trial and gene editing project. “It is a potential game changer for young sickle cell patients because the therapy eliminates the need for a suitable donor and removes the mutation for a life free of sickle cell disease.”

©Janice Haney Carr, Sickle Cell Foundation of Georgia Jackie George, Beverly Sinclair, USCDCP

Researchers are recruiting patients for treatment in California, beginning with up to six adults with sickle cell disease. A safety evaluation will be performed after the first three adult patients receive the treatment. If found to be safe and effective, it will expand to enroll three adolescents aged 12 to 17 years old. The trial is expected to last two years, with patients ideally being followed up for up to 15 years.The project team from UCSF, the Innovative Genomics Institute (IGI) and UCLA have developed CRISPR_SCD001, a patient-specific blood stem cell therapy product derived from the patient that has been modified by a CRISPR-Cas9 nuclease to stimulate repair of the sickle mutation. In the current trial, the patient’s blood stem cells will be extracted and sent to UCLA’s Human Gene and Cell Therapy Facility to be processed using electrical pulses that create temporary pores in their membranes. These pores allow the non-viral CRISPR-Cas9 platform to enter the cells and travel to the nucleus, where it corrects the sickle cell mutation before the cells are returned to the patient in a bone marrow transplant procedure.
“The use of CRISPR gene editing to fix the sickle cell disease-causing mutation in each patient’s own blood-forming stem cells required the development of new methods to produce more than 100 million cells per patient that are gene-corrected, healthy and pure,” said Donald Kohn, MD, a distinguished professor of microbiology, immunology and molecular genetics and of pediatrics at UCLA. “This represents a significant increase in scale from prior research that was limited to producing 1 to 2 million genetically corrected cells.” The trial is part of a UC research consortium led by UCSF with UCLA and UC Berkeley. It will combine CRISPR technology developed at IGI – a joint UC Berkeley-UCSF initiative founded by Nobel Laureate Jennifer Doudna – with UCLA’s expertise in genetic analysis and cell manufacturing, as well as its clinical excellence in the field, and nearly 50 years of expertise at Benioff Children’s Oakland in sickle cell care, including cord blood and marrow transplantation, and gene therapy. The trial is supported by the California Institute for Regenerative Medicine (CIRM), and NIH Cure Sickle Cell Initiative, National Heart, Lung, and Blood Institute (NHLBI).