Zinc Finger Nuclease-Mediated Gene Editing in Hematopoietic Stem Cells Results in Reactivation of Fetal Hemoglobin in Sickle Cell Disease

Document Type

Article

Publication Date

10-16-2024

Publication Title

Sci Rep

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.

Medical Subject Headings

Anemia, Sickle Cell; Fetal Hemoglobin; Humans; Gene Editing; Hematopoietic Stem Cells; Zinc Finger Nucleases; Female; Male; Adult; Hematopoietic Stem Cell Transplantation; Animals; Mice; Repressor Proteins

PubMed ID

39414860

Volume

14

Issue

1

First Page

24298

Last Page

24298

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