Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease
BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.
Authors
- John F. Tisdale (ORCID: https://orcid.org/0000-0002-8535-9439)
- Timothy Harris
- Lin Wang (ORCID: https://orcid.org/0000-0001-5994-4880)
- Hui Ling (ORCID: https://orcid.org/0000-0002-0066-6801)
- Richard Boismenu (ORCID: https://orcid.org/0000-0002-0570-3720)
- Kevin M. Moran (ORCID: https://orcid.org/0000-0002-9228-1131)
- Samuel Lessard (ORCID: https://orcid.org/0000-0002-1010-2268)
- Mehrdad Abedi (ORCID: https://orcid.org/0000-0003-4640-0977)
- Naoya Uchida (ORCID: https://orcid.org/0000-0001-6322-8991)
- Alexandra Hicks (ORCID: https://orcid.org/0000-0002-0302-5073)
- Pablo Rendo
- Bettina M. Cockroft
- Mark C. Walters (ORCID: https://orcid.org/0000-0002-6515-4559)
- Andreas Reik
- Benjamin Hsu (ORCID: https://orcid.org/0000-0002-0718-213X)
- Lakshmanan Krishnamurti (ORCID: https://orcid.org/0000-0003-3242-0037)
- Asif Alavi
- Dana N. Levasseur
- Isobelle Galeon
- Robert Peters (ORCID: https://orcid.org/0000-0002-1442-3907)
- Pauline Rimmelé
- Anne Ramezi
- Benjamin Vieira (ORCID: https://orcid.org/0009-0003-5154-5545)
- Gaurav Manohar Rajani (ORCID: https://orcid.org/0000-0002-9827-8304)
- Michael Chen (ORCID: https://orcid.org/0000-0001-7897-7733)
- David J. Reiner (ORCID: https://orcid.org/0000-0002-0344-7161)
- Yi-Dong Lin
- Vu Hong
Institutions
- National Institutes of Health (US)
- Emory University (US)
- University of California, San Francisco (US)
- Henry Ford Hospital (US)
- Sanofi (France) (FR)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- National Heart, Lung, and Blood Institute (US)
- Sanofi (United States) (US)
- Aflac (United States) (US)
- UCSF Benioff Children's Hospital (US)
- Sangamo BioSciences (United States) (US)
- Children's Healthcare of Atlanta (US)
- University of California Davis Medical Center (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1038/s41598-024-74716-7
- Citations
- 13
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.69
Funders
- Sanofi
- Biogen
- Sangamo Therapeutics