Prime Editing for p47^phox-Deficient Chronic Granulomatous Disease

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.