Implementing a First-in-Human Clinical Trial of Prime-Editing Gene Therapy in p47-CGD: Clinical Data and Site Perspectives
TL;DR
While the patient’s clinical course was simple, setting up the clinical trial required acrobatics and coordination worthy of a hyperactive octopus, implementing a first-in-human therapy for patients whose lives are not immediately at risk represents a high degree of complexity.
Abstract
In April 2025, CHU Sainte-Justine performed the world’s first gene therapy using prime editing. The patient was an 18-year-old male with autosomal recessive p47phox chronic granulomatous disease (CGD). Infectious history included osteomyelitis, abscesses, and Burkholderia cepacia pneumonia. He also had an active colitis with intermittent oral ulcers, managed with Pentasa. An allogeneic hematopoietic cell transplantation (HCT) had been dismissed during childhood in the absence of a compatible donor. At fall 2024, the opportunity arose for the patient to enroll in this gene therapy clinical trial to achieve a permanent cure for his disease. After completing the screening, apheresis, and busulfan conditioning phases, the patient received the investigational product, PM359, manufactured from autologous CD34+ cells in which the GT deletion in NCF1 was corrected using prime editing. Aside from mild adverse events related to busulfan conditioning, no serious events occurred. Neutrophil engraftment was achieved on Day 16 and platelet engraftment on Day 19. NADPH oxidase activity in neutrophils, measured by dihydrorhodamine (DHR), increased from less than 1% pre-infusion to 69% by Day 30. To this day (9 months post-infusion), the DHR remains stable at 77%, and the patient has no CGD manifestations and is no longer on medication. Another 57-year-old patient with a long history of infections of lung, liver, and lymph nodes plus inflammatory bowel disease (IBD) received the same treatment at the National Institutes of Health (NIH), and the outcome was also excellent and uneventful. The DHR normalized for 83% of neutrophils, and this result was stable after 6 months. He is no longer on prophylactic antibiotics, and his IBD has significantly improved. While our patient’s clinical course was simple, setting up the clinical trial required acrobatics and coordination worthy of a hyperactive octopus. Implementing a first-in-human therapy for patients whose lives are not immediately at risk represents a high degree of complexity. This success required nearly two years of preparation, from initial contact with the trial sponsor to PM359 administration. Through the preparation of the site qualification and audit days, it was essential to surround ourselves with the right resources—within the cell therapy laboratory, the apheresis unit, and the quality assurance team. Beyond having those resources in order, one must know how to present them, clarify them, and adapt to the sponsor’s requests, while ensuring compliance with existing procedures. We orchestrated the treatment plan with our clinical teams to align as closely as possible with standard practice while anticipating tools to mitigate uncertainty when deviations were necessary and making sure no one was overlooked: nurses, physicians, nutritionists, laboratories, pharmacy, imaging, and more. In parallel, we had to prepare a robust ethics submission and a consent form that says everything—without being overwhelming. Finally, it culminated in presenting the trial to the patient and his parents and guiding their decision-making, leading to the results presented above. Our objective is to present the outcome of those patients together with the description of all the steps of the clinical trial, likely including a video testimony of our patient.