Novel Gene Therapy Trial for Sickle Cell Disease Launches

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.

Sickle cell disease is a genetic blood disorder caused by a single mutation in both copies of a gene coding for beta-globin. Beta-globin forms half of the oxygen-carrying molecule hemoglobin. This mutation causes hemoglobin molecules to stick together, deforming red blood cells into a characteristic “sickle” shape. These malformed cells get stuck in blood vessels, causing blockages, anemia, pain, organ failure and a significantly shortened lifespan. Sickle cell disease affects approximately 100,000 Americans and millions worldwide, with a disproportionate effect on the Black community.
 
UCSF’s 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,” said 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.”

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 for up to 15 years.

100 million gene-corrected cells per patient

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 CRISPR-Cas9 platform to enter the cells and travel to the nucleus without the use of a viral vector. Once in the nucleus, 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 concept for this therapy started from a conversation I had with Mark Walters around 10 years ago, so it’s gratifying to see it advance to a clinical trial,” said Doudna, PhD, the Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences at UC Berkeley. “I’m hopeful for a future with more affordable, accessible, and safer cures for sickle cell disease, and this is an important step in that direction.”

This clinical study continues BCH Oakland’s commitment to treating and finding a cure for sickle cell disease. The Comprehensive Sickle Cell Disease Center was created at the hospital in 1973 to provide expert diagnosis, treatment and long-term health management for children and adults with sickle cell disease. Now known as the BCH Oakland Sickle Cell Center of Excellence, it is recognized as having one of the largest and most comprehensive sickle cell programs in the Western U.S.

Funding: 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).

UCSF Benioff Children’s Hospitals are among the nation’s leading pediatric specialty hospitals, according to U.S. News & World Report rankings. Their expertise covers virtually all pediatric conditions, including cancer, heart disease, neurological disorders, pulmonology, diabetes and endocrinology, as well as the care of critically ill newborns. The two campuses in San Francisco and Oakland are known worldwide for basic and clinical research and are at the forefront of translating research into interventions for treating and preventing pediatric disease. They are part of UCSF Health, whose adult hospital ranks among the top 10 medical centers nationwide and serves as the teaching hospital for the University of California, San Francisco, a national leader in biomedical research and graduate-level health/sciences education. Visit ucsfhealth.org.