Prime Editing for p47 <sup>phox</sup> -Deficient Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) is a severe monogenic immunodeficiency caused by damaging variants in genes required for microbicidal NADPH oxidase activity. Autosomal recessive p47<sup>phox</sup>-deficient CGD (p47-CGD) is predominantly caused by a two-nucleotide deletion in exon 2 (delGT) of <i>NCF1</i>. 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.).
Authors
- Briana Deary
- Emma Morris (ORCID: https://orcid.org/0000-0003-4834-1130)
- Meghann McManus
- Harry L. Malech (ORCID: https://orcid.org/0000-0001-5874-5775)
- Douglas B. Kuhns (ORCID: https://orcid.org/0000-0002-9971-0760)
- David P. Waterman
- Haydar Frangoul (ORCID: https://orcid.org/0000-0002-0590-2826)
- Pierre Teira (ORCID: https://orcid.org/0000-0002-6358-3771)
- Karine Léveillé
- Jacob Stewart-Ornstein (ORCID: https://orcid.org/0000-0001-8255-5904)
- Ben Carpenter
- Stuart E. Turvey (ORCID: https://orcid.org/0000-0003-1599-1065)
- Mike Nickerson
- Andrew V. Anzalone (ORCID: https://orcid.org/0000-0003-2531-5589)
- Donald B. Kohn (ORCID: https://orcid.org/0000-0003-1840-6087)
- Patricia Littel
- Ronja Victoria Scholz
- Debra A. Long Priel (ORCID: https://orcid.org/0000-0002-9434-4503)
- Alexandria Petrusich
- Mohammed Asmal (ORCID: https://orcid.org/0009-0002-9834-1286)
- Tiernan T. O’Malley
- Élie Haddad (ORCID: https://orcid.org/0000-0003-2446-6879)
- Jennifer L. Gori (ORCID: https://orcid.org/0000-0003-2824-5547)
- Misty Evans
- Suk See De Ravin (ORCID: https://orcid.org/0000-0002-9800-774X)
- Elizabeth M. Kang
- Isabel Fernández
- Tyra Estwick
- James E. Arnold
- Barrett J. Nehilla
- Bradley J. Martin
- Jack Heath
- Marie Pierzynski
- Christa E Osuna
Institutions
- Leidos (United States) (US)
- National Institutes of Health (US)
- University College London Hospitals NHS Foundation Trust (GB)
- University of British Columbia (CA)
- University of California, Los Angeles (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- National Institute for Health and Care Research (GB)
- Children’s Hospital at TriStar Centennial (US)
- Frederick National Laboratory for Cancer Research (US)
- National Institute of Allergy and Infectious Diseases (US)
- BC Children's Hospital (CA)
- University College London (GB)
Publication Details
- Journal
- New England Journal of Medicine
- Published
- 2025-12-07
- DOI
- https://doi.org/10.1056/nejmoa2509807
- Citations
- 4
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.19