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Prime Editing for p47phox-Deficient Chronic Granulomatous Disease
Jennifer L Gori1, Elie Haddad2,3, Haydar Frangoul4
1Prime Medicine, Cambridge, MA.
Abstract:
Chronic granulomatous disease (CGD) is a severe monogenic immunodeficiency caused by damaging variants in genes required for microbicidal NADPH oxidase activity. Autosomal recessive p47phox-deficient CGD (p47-CGD) is predominantly caused by a two-nucleotide deletion in exon 2 (delGT) of NCF1. We developed PM359, an autologous CD34+ hematopoietic stem-cell therapy in which prime editing is used to correct delGT. Two participants received PM359 after myeloid conditioning with busulfan: neutrophils and platelets engrafted promptly in both patients. Adverse events were consistent with myeloid conditioning with busulfan. NADPH oxidase activity was observed in neutrophils within 1 month and was maintained for 6 months and 4 months as of the last follow-up visit in Participants 1 and 2, respectively. These results support further investigation of prime editing of CD34+ cells to treat p47-CGD. (Funded by Prime Medicine; ClinicalTrials.gov number, NCT06559176.).
Insights
Prime editing successfully corrected a genetic defect in hematopoietic stem cells for two patients with p47-phox-deficient chronic granulomatous disease (CGD). This innovative therapy restored crucial NADPH oxidase activity in neutrophils, offering hope for CGD treatment.
Area of Science:
- Genetics
- Immunology
- Hematology
Background:
- Chronic granulomatous disease (CGD) is a severe inherited immunodeficiency.
- It stems from mutations impairing NADPH oxidase function, crucial for pathogen killing.
- Autosomal recessive p47-phox-deficient CGD (p47-CGD) is often caused by the NCF1 gene's delGT mutation.
Purpose of the Study:
- To evaluate the safety and efficacy of PM359, a novel autologous CD34+ hematopoietic stem cell therapy.
- PM359 utilizes prime editing to correct the delGT mutation in the NCF1 gene.
- To assess the restoration of NADPH oxidase activity in patients with p47-CGD.
Main Methods:
- Development of PM359, an autologous CD34+ cell therapy using prime editing.
- Administration of PM359 to two participants with p47-CGD following busulfan-based myeloid conditioning.
- Monitoring of neutrophil and platelet engraftment, adverse events, and NADPH oxidase activity post-transplantation.
Main Results:
- Prompt engraftment of neutrophils and platelets was observed in both participants.
- Adverse events were consistent with standard busulfan conditioning.
- Restored NADPH oxidase activity in neutrophils was detected within one month and sustained for at least 4-6 months.
Conclusions:
- Prime editing of CD34+ hematopoietic stem cells is a promising strategy for treating p47-CGD.
- The study supports further clinical investigation of this gene-editing approach.
- Successful correction of the genetic defect and functional recovery were demonstrated.
