First in human prime edited autologous hematopoietic stem cell therapy for the treatment of p47phox CGD: Initial results of PRIME-0101

Abstract P47phox deficient phagocytic oxidase Chronic Granulomatous Disease (p47phox CGD) is an inherited immunodeficiency caused by mutations in the NCF1 gene which encodes the p47phox protein, a subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which is a critical first line of innate immune system defense against bacterial and fungal pathogens. The mutation in NCF1 prevents NADPH oxidase production of oxidative bursts that destroy pathogens and control infection. Individuals with p47phox CGD experience recurrent severe infections, and inflammation of multiple organs, most notably the bowel, lung, liver and genitourinary system. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential cure, but is associated with significant limitations due to donor availability, and the risks of transplant related morbidity and mortality including graft failure, graft-versus-host disease and post-transplant immunosuppression. The prevalent causative mutation giving rise to p47phox CGD is the ‘delGT’ dinucleotide deletion in exon 2 of the NCF1 gene. The NCF1 locus is complex as the gene encoding p47phox is flanked by two nearly identical nonfunctional pseudogenes which bear the inactivating delGT mutation. Prime Editing is uniquely well-suited to correct the delGT NCF1 variant, both because of its versatile ability to precisely replace targeted and specific DNA sequences, and because it does not induce double-strand breaks, which carry the risk of chromosomal instability at this complex locus. PM359 is an autologous CD34+ hematopoietic stem cell suspension drug product that is Prime Edited at the NCF1 locus resulting in correction of the delGT mutation. In preclinical studies, >80% of p47phox CGD CD34⁺ cells were Prime Edited to precisely correct the delGT mutation. The Prime Edited corrected p47phox CGD CD34+ cells reconstituted human hematopoiesis in NBSGW immunodeficient mice and the frequency of engrafted precisely corrected Prime Edited p47phox CGD CD34+ cells remained stable for 16 weeks in vivo, resulting in quantitative restoration of NADPH oxidase activity, with no perturbation of multilineage human blood production, no detectable off-target edits, and no detectable chromosomal alterations (a result that contrasts to CRISPR nuclease editing at this locus). Prime-0101 is a first-in-human study of PM359 in adult and pediatric participants with p47phox CGD. Two study participants, Participant 1 (18yo male) and Participant 2 (57yo male) underwent HSC mobilization with G-CSF and plerixafor, and the apheresis product was transferred to a central manufacturing facility to generate PM359. Study participants received myeloablative conditioning with targeted busulfan prior to infusion of PM359. Both Participants achieved rapid neutrophil engraftment at 13 and 19 days and platelet engraftment at 14 and 12 days respectively following infusion of PM359. By one month after treatment, 69% of Participant 1's and 80% of Participant 2's peripheral neutrophils expressed normal levels of NADPH oxidase activity as measured by the dihydrorhodamine (DHR) assay. These results correlated to the frequency of Prime Edited CD34+ cells measured in the drug products (Participant 1: 68% and Participant 2: 91% Prime Edited colony forming cells). DHR results for Participant 1 have remained stable through month 3. Importantly, frequency of both DHR+ neutrophils and Prime Edited CD34+ cells exceed the 20% threshold expected to be sufficient for restoration of NADPH oxidase anti-pathogen activity and amelioration of disease pathology. Safety was consistent with busulfan conditioning; neither participant required platelet or red blood cell transfusion support. The initial results from the Prime-0101 study provide the first-in-human demonstration of the safety and efficacy of Prime Editing and offer an autologous cell therapy for individuals with p47phox CGD.

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