A publicly funded consortium of University of California (UC) researchers and clinicians is one big step closer to realizing a decade-long plan to launch a CRISPR-based gene-editing trial for sickle cell disease (SCD). Last week, the team, led by 2020 Nobel laureate Jennifer Doudna, PhD, announced plans to recruit the first six patients into a clinical trial that is entirely publicly funded.
The CRISPR-SCD trial—so much for a catchy acronym—is the first clinical attempt to use a non-viral delivery approach to directly correct the SCD mutation.
Spearheading the project alongside Doudna (Innovative Genomics Institute, UC Berkeley/Howard Hughes Medical Institute) are a pair of veteran pediatric bone marrow transplant physicians, Mark Walters, MD (UC San Francisco) and Donald Kohn, MD (UC Los Angeles).
Walters is the director of the Pediatric Blood and Marrow Transplant Program at UCSF Benioff Children’s Hospital in Oakland. “When all you have is bone marrow transplantation, the nail includes sickle cell disease,” he told GEN.
The collaborative UC project was initiated about a decade ago, when Doudna approached Walters to discuss the use of CRISPR as a potential curative therapy for SCD patients. Walters admits he didn’t know anything about CRISPR at the time. “My learning curve has been steep!” he said.
“We thought we were hopelessly behind” the competition, Walters said. But he recalls Doudna saying, “Well, we have some tricks up our sleeves, we think we’ll catch up quickly.” The approach she favored involved using a DNA repair pathway called homology-directed repair (HDR) to correct the sickle cell point mutation directly, rather than the fetal globin switching approach favored by Vertex Pharmaceuticals.
Walters says it was not his team’s intent to eschew commercial support. There were conversations, he says, with an offshoot of Synthego, but nothing materialized. The overarching priority has been accessibility. “Finding something that we can make accessible to patients is really important,” he said.
Cutting edge
CRISPR-SCD is using the same editor as a long-standing approach led by Matthew Porteus, MD, PhD, and his new company, Kamau Therapeutics. But an important distinction is the choice of delivery vehicle. Whereas the Porteus group has favored using adeno-associated virus 6 (AAV6) for delivery, the UC consortium is using a single-stranded oligonucleotide donor. “We tested both head-to-head and we landed on the oligonucleotide, because the AAV6 was a little unreliable and it was very toxic to the stem cells,” Walters said.
The Cas9 nuclease cleaves the β-globin gene about 15 basepairs downstream from the SCD point mutation. Walters and his colleagues, including Mark DeWitt PhD, published their first proof-of-concept study in 2016, identifying the optimal single-guide RNA for gene editing, even if the correction rate was a modest 2–3 percent. Six years later, using a hi-fi Cas9, the team reported a much-improved editing efficiency of 25–30 percent.
Walters believes that threshold should be clinically sufficient, in the wake of observations on allogeneic bone marrow transplantation, which has shown that “you don’t need 100% donor cells to correct the disease because of the natural enrichment of those donor cells in the bloodstream. So 20–25% is probably the minimum [we need] and that’s where we are now.”
“It is really an important question: Is that going to be sufficient for a curative effect? I think it will make things better but will it actually eliminate all the signs and symptoms? That’s what we’re going to learn.” The editing threshold hinges in part on the success of the electroporation step, which will take place at UCLA.
Walters intuitively favors the direct approach rather than the Vertex approach of switching on fetal hemoglobin (HbF) by interfering with BCL11A expression or function, though he admits it is more about intuition than empirical reasoning. “What is BCL11A doing besides just repressing fetal hemoglobin in erythropoiesis? So far, that seems to be the only thing, but it’s necessary for B-cell development, for stem cell development, so what else is it doing?” Walters asks rhetorically. While Casgevy and other approaches in the clinic seem “safe and durable,” the caveat “sits in the back of my mind as a concern. Hopefully, it will never come to reality.”
Take nothing away from Casgevy’s clinical success, Walters says. In the 1980s, a major natural history study of SCD revealed that there might be a threshold HbF level needed to eliminate pain in patients. But even incremental increases of HbF could be clinically important.
“I was expecting something like that [in the Casgevy trial] where you’d get incrementally improved pain but not eliminated. So seeing it completely eliminated in 90+ percent of the participants was really spectacular.” (Walters is a member of the Vertex steering committee for the exa-cel trial, but did not directly manage patients.) He also was one of the leaders of the Bluebird bio Lyfgenia gene therapy trial, with Julia Kanter, MD, and John Tisdale, MD.
Courage and responsibility
Walters’ team is now recruiting half-a-dozen patients, 18–35 years old, who will be treated at UCLA or UCSF. If the first phase demonstrates safety and efficacy, the next plan is to recruit three more patients, adolescents between 12 and 17.
Walters feels a sense of responsibility. “This is a first-in-human trial where we don’t have any [clinical] data to refer to. So it requires a fair amount of courage and trust to get to the point where [volunteers] want to pursue it. We’re still waiting to find those rare, courageous people to be pioneers and join.”
The Benioff Children’s Hospital in Oakland used to be a standalone children’s hospital but was acquired by UCSF in 2014. UCSF has embarked on an ambitious capital project to build a new $1.5-billion state-of-the-art hospital, with a planned opening in 2031.
Even though access is challenging, Walters is putting much of his energy into making sure that this protocol gets developed and “we can deliver a safer curative therapy.” Walters says “you roll the dice every time you do” a bone marrow transplant. “It’s terrifying as a provider, because they aren’t going to die of their sickle cell disease, probably for some time, and what we’ve done is shorten their life… So it’s a huge responsibility, even though some of these things are unavoidable.”
“We’re going to learn a lot” in 2025, Walters says. Down the road, the development of the therapy may involve emerging philanthropic-industry partnerships that are “aimed at accessibility and lowering the cost of manufacturing, passing on those savings directly to patients. That model is something that looks attractive.”
