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Abstract
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.
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Details
1 Rare Blood Disorders, Sanofi, Waltham, USA (GRID:grid.417555.7) (ISNI:0000 0000 8814 392X); Sanofi, Precision Medicine and Computational Biology, Cambridge, USA (GRID:grid.417555.7) (ISNI:0000 0000 8814 392X)
2 Rare Blood Disorders, Sanofi, Waltham, USA (GRID:grid.417555.7) (ISNI:0000 0000 8814 392X)
3 Sangamo Therapeutics, Richmond, USA (GRID:grid.421831.d) (ISNI:0000 0004 0410 9476)
4 National Heart, National Institutes of Health (NIH), Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165)
5 Henry Ford Cancer Institute, Detroit, USA (GRID:grid.446722.1) (ISNI:0000 0004 0635 5208)
6 Children’s Healthcare of Atlanta, Emory University, Aflac Cancer and Blood Disorders Center, Atlanta, USA (GRID:grid.428158.2) (ISNI:0000 0004 0371 6071)
7 University of California-Davis Medical Center, Sacramento, USA (GRID:grid.413079.8) (ISNI:0000 0000 9752 8549)
8 University of California San Francisco Benioff Children’s Hospital, Oakland, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
9 Rare Blood Disorders, Sanofi, Waltham, USA (GRID:grid.417555.7) (ISNI:0000 0000 8814 392X); Sanofi, Immunology and Inflammation, Cambridge, USA (GRID:grid.417555.7) (ISNI:0000 0000 8814 392X)