Conversion of HbS to Hb G-Makassar By Adenine Base Editing Is Compatible with Normal Hemoglobin Function

S. Haihua Chu, Manuel Ortega, Paty Feliciano,Valerie Winton, Chavonna Xu,Daniel Haupt, Teresa McDonald, Salette Martinez,Alexander Liquori,Jeffrey Marshall,Daisy Lam,Jenny Olins,Conrad Rinaldi, Kyle Rehberger, Colin Lazarra,Jeremy Decker,Bob Gantzer,Tanggis Bohnuud,David Born,Luis Barrera

Blood(2021)

引用 6|浏览15
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摘要
Conversion of the pathogenic sickle allele to a naturally occurring, non-pathogenic hemoglobin variant, Hb G-Makassar, represents a long-term and durable treatment strategy for sickle cell disease (SCD). Using our engineered adenine base editor, we achieved highly efficient base editing in mobilized sickle trait (HbAS) and non-mobilized homozygous sickle (HbSS) CD34 + cells that led to >70% conversion of sickle allele to Makassar allele in in vitro erythroid differentiated (IVED) cells derived from ex vivo edited CD34 + cells. At this level of editing, >70% bi-allelic Makassar editing could be achieved in HbSS IVED cells, with ~20% of cells being mono-allelically Makassar edited. These mono-allelically edited cells behaved similarly to sickle trait (HbAS) cells, when exposed to hypoxic conditions in vitro. In vivo proof of concept xenotransplantation studies demonstrated that Makassar edited HbAS CD34 + cells achieved long-term, multi-lineage hematopoietic engraftment as well as Makassar globin protein expression in human erythroid glycophorin A + cells in thebone marrow of immunocompromised mice.
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