UCSF researchers hope to cure sickle cell disease through CRISPR gene editing
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With the aid of $17 million in grant funding, UCSF Benioff Children’s Hospital Oakland will initiate a 4-year trial evaluating CRISPR/Cas9 gene editing as a potential cure for sickle cell disease.
Researchers at the institution have received a grant of $8.4 million from the California Institute for Regenerative Medicine and one of $8.6 million from the NIH Cure Sickle Cell Initiative, which NHLBI sponsors, to support the trial.
“It’s important to acknowledge that we got funding to do this clinical trial from the National Institutes of Health and the California Institute of Regenerative Medicine,” Mark Walters, MD, professor of pediatrics at UCSF and principal investigator of the clinical trial and gene-editing project, said in an interview with Healio. “It’s a substantial contribution, because insurance does not cover the care we deliver as part of the trial, so most of our budget goes to the 6 weeks the patients have to spend in the hospital when they receive this investigative therapy.”
Modifying cell mutation
The trial is part of a UC Research consortium UCSF leads in collaboration with UCLA and UC Berkeley. It will initially enroll up to six adults with sickle cell disease from sites in Oakland and Los Angeles and, upon meeting safety and efficacy endpoints, expand to include three adolescents aged 12 to 17 years. Seven patients will be treated in Oakland and two in Los Angeles.
The trial marks the first to assess the use of nonvirally delivered CRISPR gene-editing tools to correct a harmful beta-globin gene mutation in a patient’s own cells. Walters said the project began when he and colleagues met with Jennifer Doudna, PhD, who along with Emmanuelle Charpentier, PhD, won the 2020 Nobel Prize in chemistry for discovering CRISPR technology.
“After that meeting, we decided to optimize the gene editing reagents and cell lines, and we were able to do that rather quickly. Then we recruited a third scientist, Donald Kohn, MD, who is at UCLA and is an expert in manufacturing for gene therapy and gene-editing trials. So, it’s a disease team of experts in sickle cell disease, gene therapy, manufacturing and gene editing.”
Sickle cell disease is a genetic condition that impacts the structure and function of hemoglobin, decreases red blood cells’ capacity to efficiently circulate oxygen, and ultimately advances to a chronic vascular disease. Approximately 100,000 Americans live with sickle cell disease, with Black individuals disproportionately affected.
“The hallmark of sickle cell disease is pain, which occurs when the patient doesn’t have enough oxygen or blood flow, but it affects virtually every organ in the body and can cause stroke,” Walters told Healio. “It leads to a 30-year decrement in lifespan of those who inherit the disease. Although there are disease-modifying treatments — pills and other therapies that patients receive daily or monthly as a lifelong treatment — this would offer the possibility of using one’s own stem cells. So, patients would not need to find donors, but would use their own stem cells that have been modified to eliminate the mutation.”
Use of nonviral reagents
A single-letter mutation in human DNA causes sickle cell disease. The trial will utilize CRISPR genome editing to correct the mutation directly.
In the current trial, researchers will extract a patient’s blood stem cells and send them to UCLA’s gene manufacturing lab to be processed. They will use electrical pulses to create temporary pores in the cells’ membranes. This will facilitate entry of the CRISPR/Cas9 platform into the cells and, ultimately, into the nucleus, where it corrects the cell mutation before being returned to the patient.
“What’s unique about this is that we use nonviral reagents to accomplish the gene editing.” Walters said. “The treatment itself is introducing those gene editing reagents, the CRISPR tools, including the Cas9, and then the guide RNA that directs that editing of the sickle mutation DNA. We also provide all of the nucleotide, which is a single-stranded piece of DNA — a short piece of DNA that acts as the template to lay down the correct sequence and repair the mutation.”
The trial will utilize CRISPR technology that originated from the Innovative Genomics Institute (IGI), a UC Berkley-UCSF collaboration Doudna founded. A project team from UCSF, the IGI and UCLA have developed CRISPR_SCD001, a patient-specific blood stem cell therapy that has been modified by a CRISPR/Cas9 nuclease to promote repair of the sickle mutation.
Walters noted that although the technology has considerable promise for treating sickle cell disease, the trial is a first-in-human study focused on safety.
“This is a proof-of-principle step, where we first show that you can use CRISPR safely in blood stem cells from people with this disorder,” Walters told Healio. “We think it will be a safer and even more effective application of the CRISPR technology.”
Walters and his colleagues are hopeful the trial will have positive implications for the future treatment of sickle cell disease.
“I hope this is the first in a series, at the end of which we will have a readily available, effective and safe therapy,” he said. “I have a lot of confidence that we will end with something that will be very exciting and potentially broadly available.”
For more information:
Mark Walters, MD, can be reached at UCSF Benioff Children’s Hospital, 747 52nd St., Oakland, CA 94609; email: mark.walters@ucsf.edu.
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