Trial of gene-editing therapy into SCD’s cause opens in California
Phase 1/2 study to test CRISPR_SCD001 in people with severe disease
Two centers in California are enrolling nine people with severe sickle cell disease (SCD) for a clinical trial of a new gene editing therapy called CRISPR_SCD001.
The Phase 1/2 trial (NCT04774536) is open to adolescents and adults, ages 12 through 35, who in the two years before enrollment had at least four severe vaso-occlusive events, and two or more episodes of acute chest syndrome. Eligible patients also must be able to care for themselves, and show evidence of good heart, lung, kidney, and liver function.
Initially, the study will test the infusion therapy in three adult patients, one after the other, with safety reviews following each treatment. If all goes well, three more adults will be treated. If safety again is found, CRISPR_SCD001 then will be given to three adolescents.
“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 and the trial’s principal investigator at the University of California San Francisco, said in a university news story. “It is a potential game changer for young sickle cell patients.”
Gene editing for sickle cell aims to restore healthy hemoglobin production
The investigator-sponsored and open-label trial is expected to last two years, with patients potentially being followed for up to 15 years. Its main goal is to assess the safety of the therapy. Secondary goals include evaluating the effects of CRISPR_SCD001 on the rates of vaso-occlusive events, as well as on the levels of specific disease biomarkers.
Enrollment is underway at one center in Los Angeles and another in Oakland. Additional details, including contact information, are available on the study’s website.
SCD is caused by mutations in the HBB gene, which provides instructions to make part of hemoglobin — the protein that red blood cells use to carry oxygen through the body. These mutations lead to the production of an abnormal form of hemoglobin that deforms red blood cells into a sickle-like shape. The misshapen cells are prone to getting trapped inside blood vessels and blocking blood flow, triggering events like vaso-occlusive crises and acute chest syndrome.
CRISPR_SCD001, developed by scientists in the University of California system and those at the Innovative Genomics Institute, uses the CRISPR-Cas9 gene-editing technology to replace a patient’s mutated HBB gene with a healthy copy of the gene. The therapy aim is to restore the production of healthy hemoglobin.
“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 Jennifer Doudna, PhD, a researcher at the University of California Berkeley, and founder of the genomics institute who shared a Noble Prize for developing the CRISPR-Cas9 technology. “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.”
CRISPR_SCD001 aims to correct the SCD-causing mutation in blood cells
CRISPR_SCD001 involves collecting blood stem cells from a patient’s bone marrow, using the gene-editing technology in a lab to correct the disease-causing mutation in these cells before returning them to the patient via a bone marrow transplant.
“The therapy … removes the mutation for a life free of sickle cell disease,” Walters said.
CRISPR_SCD001 is somewhat similar to Casgevy (exagamglogene autotemcel), the first CRISPR/Cas9 gene-editing treatment to win approval in the U.S. Casgevy uses gene editing to increase production of fetal hemoglobin, an alternative form of hemoglobin, while CRISPR_SCD001 aims to correct the gene whose mutation causes SCD. Unlike Casgevy and other gene-editing therapies in development, CRISPR_SCD001 also does not use a viral vector to deliver the gene-editing machinery to cells. Instead, gene-editing components enter cells through temporary pores created in the cell membrane by electrical pulses.
With both Casgevy and CRISPR_SCD001, patients need undergo a round of high-dose chemotherapy prior to the infusion to kill off unhealthy cells in the bone marrow and make room for the edited new ones.
The trial is supported by the California Institute for Regenerative Medicine, and the Cure Sickle Cell Initiative led by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.
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