Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease

Authors

• Ashish O Gupta
• Akshay Sharma
• Haydar Frangoul
• Julie Kanter
• Markus Y Mapara
• Jignesh Dalal
• Asif Alavi, Henry Ford HealthFollow
• Jennifer J Jaroscak
• Ernesto Ayala
• John F DiPersio
• Edward D Ziga
• Mary Eapen
• Stacey Rifkin-Zenenberg
• Alex C Minella
• Yinzhong Chen
• Sarah Chesler
• Srikanth Ambati
• Thomas S Bowman
• Bahru Habtemariam
• Marcelyne Joseney-Antoine
• Priya S Chockalingam
• Ling Lin
• Sunita Goyal
• Amy Simon
• Alexis A Thompson
• Matthew M Heeney

Recommended Citation

Gupta AO, Sharma A, Frangoul H, Kanter J, Mapara MY, Dalal J, Alavi A, Jaroscak JJ, Ayala E, DiPersio JF, Ziga ED, Eapen M, Rifkin-Zenenberg S, Minella AC, Chen Y, Chesler S, Ambati S, Bowman TS, Habtemariam B, Joseney-Antoine M, Chockalingam PS, Lin L, Goyal S, Simon A, Thompson AA, Heeney MM. Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease. N Engl J Med. 2026.

Document Type

Article

Publication Date

4-1-2026

Publication Title

The New England journal of medicine

Abstract

BACKGROUND: Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF).

METHODS: In this phase 1-2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×10(6) viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion.

RESULTS: A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion.

CONCLUSIONS: Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).

PubMed ID

41931046

ePublication

ePub ahead of print