In a small sample of patients, the CRISPR–Cas9–edited CD34+ hematopoietic stem- and progenitor-cell therapy showed expected safety while inducing red cell fetal hemoglobin.
Data from a phase 1/2 trial (NCT04443907) in individuals with severe complications of sickle cell disease (SCD) suggest that treatment with OTQ923, a CRISPR–Cas9–edited CD34+ hematopoietic stem- and progenitor-cell (HSPC) agent developed by Novartis, is able to effectively induce red cell fetal hemoglobin.1,2 Additionally, signs of clinical improvement in disease severity were observed in this small cohort effort.1
This study included 3 individuals (referred to as Participants 1-3) who were treated with autologous OTQ923 after myeloablative conditioning and followed for 6 to 18 months. All told, each of these individuals had engraftment stable induction of fetal hemoglobin at the end of follow-up (percentage of total hemoglobin, 19% to 26.8%) and broad distribution of fetal hemoglobin in red cells (percentage of red cells, 697.7% to 87.8%). Several adverse events (AEs) were observed, but the investigators deemed them to be related to either myeloablative busulfan conditioning or underlying SCD, and unrelated to OTQ923.
Study author James LaBelle, MD, PhD, and colleagues noted that SCD manifestations were reported to have decreased after administration as well, though all 3 participants experienced at least 1 SCD-related event. Participant 1 had a vaso-occlusive crisis linked to back and leg pain that acute chest syndrome 17 months post infusion; Participant 2 had leg pain associated with a vaso-occlusive crisis at 12 months post infusion; Participant 3 also had hip and lower-back pain associated with a vaso-occlusive crisis 9 months post infusion. Notably, participants 1 and 2 were admitted to the hospital for the management of pain episodes, and all 3 continued to have focal intermittent episodic pain in their hips and lower legs.
“The biggest take-home message is that there are now more potentially curative therapies for sickle cell disease than ever before that lie outside of using someone else’s stem cells, which can bring a host of other complications,” LaBelle, an associate professor of pediatrics and the director of the Pediatric Stem Cell and Cellular Therapy Program at UChicago Medicine and Comer Children’s Hospital, said in a statement.2 “Especially in the last 10 years, we’ve learned about what to do and what not to do when treating these patients. There’s been a great deal of effort towards offering patients different types of transplants with decreased toxicities, and now gene therapy rounds out the set of available treatments, so every patient with sickle cell disease can get some sort of curative therapy if needed. At UChicago Medicine, we’ve built infrastructure to support new approaches to sickle cell disease treatment and to bring additional gene therapies for other diseases.”
As of the data cutoff date of March 27, 2023, a total of 16 participants had consented to participate in the study, though only 3 had received OTQ923. A partial dose of OTQ923 had been manufactured but not yet infused in 4 other participants, and the remaining 9 participants were found to be ineligible, withdrew, or had not started apheresis.
To summarize the clinical outcomes of the 3 individuals for whom data were available:
Participant 1 (22-year-old man with the βS/βS genotype)
Participant 2 (21-year-old man with the βS/βS genotype)
Participant 3 (24-year-old woman with the βS/βS genotype)
About 100,000 Americans have SCD, with it affecting 1 in 365 Black babies and 1 in 16,300 Hispanic babies born in the United States, according to the Centers for Disease Control and Prevention.3 Previously, in preclinical experiments, LaBelle and colleagues wrote, “CD34+ HSPCs obtained from healthy donors and persons with SCD that were edited with CRISPR-Cas9 and gRNA-68 had sustained on-target editing with no off-target mutations and produced high levels of fetal hemoglobin after in vitro differentiation or xenotransplantation into immunodeficient mice.”
LaBelle et all explained that SCD is the result of a defect in the β-globin subunit of adult hemoglobin—sickle hemoglobin then polymerizes under hypoxic conditions, producing deformed red cells that hemolyze and causing vaso-occlusion, ultimately leading to organ damage and early death. Although, elevated fetal hemoglobin levels in red cells can protect against these complications, creating promise for OTQ923.