Research ArticleGene Therapy

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease

See allHide authors and affiliations

Science Translational Medicine  16 Jun 2021:
Vol. 13, Issue 598, eabf2444
DOI: 10.1126/scitranslmed.abf2444

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Gene correction for SCD stem cells

Sickle cell disease (SCD) is an autosomal recessive disease resulting from a point mutation in the β-globin gene that leads to sickle-shaped red blood cells, pain crises, and decreased life span. Here, Lattanzi et al. studied ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) as a potential cure for SCD. The authors demonstrated 20% gene correction after transplantation of corrected HSPCs into immunodeficient mice, with no evidence of genotoxicity or tumorigenicity. The gene-corrected HSPCs could also be reliably produced at scale. These studies lay the groundwork for a clinical trial of this gene correction strategy in patients with SCD.

Abstract

Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (HBB). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD. We previously developed a CRISPR-Cas9 gene targeting strategy that uses high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce recombinant adeno-associated virus serotype 6 (rAAV6)–mediated HBB gene correction of the SCD-causing mutation in HSPCs. Here, we demonstrate the preclinical feasibility, efficacy, and toxicology of HBB gene correction in plerixafor-mobilized CD34+ cells from healthy and SCD patient donors (gcHBB-SCD). We achieved up to 60% HBB allelic correction in clinical-scale gcHBB-SCD manufacturing. After transplant into immunodeficient NSG mice, 20% gene correction was achieved with multilineage engraftment. The long-term safety, tumorigenicity, and toxicology study demonstrated no evidence of abnormal hematopoiesis, genotoxicity, or tumorigenicity from the engrafted gcHBB-SCD drug product. Together, these preclinical data support the safety, efficacy, and reproducibility of this gene correction strategy for initiation of a phase 1/2 clinical trial in patients with SCD.

View Full Text

Stay Connected to Science Translational Medicine