Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease
| Autor: | Helen Segal, Sruthi Mantri, M. Kyle Cromer, Neehar Bhatia, Maria Grazia Roncarolo, Annalisa Lattanzi, Ciaran M. Lee, David DiGiusto, Rasmus O. Bak, Carsten T. Charlesworth, Josefin Kenrick, Jason Skowronski, Matthew H. Porteus, J. Fraser Wright, Richard L. Frock, Daniel P. Dever, Narae Talbott, Christopher A. Vakulskas, Joab Camarena, Gang Bao, Waracharee Srifa, Premanjali Lahiri, John F. Tisdale |
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| Rok vydání: | 2021 |
| Předmět: |
EXPRESSION
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities CD34 EFFICIENT Anemia Sickle Cell beta-Globins medicine.disease_cause THERAPY Article Mice 03 medical and health sciences DOUBLE-STRANDED BREAKS 0302 clinical medicine Heterocyclic Compounds hemic and lymphatic diseases medicine Animals Humans Progenitor cell HEMOGLOBIN Gene CURE Gene Editing Mutation business.industry CRISPR-Cas Systems/genetics Reproducibility of Results Gene targeting General Medicine Hematopoietic Stem Cells BONE-MARROW-TRANSPLANTATION Hematopoietic Stem Cell Mobilization Anemia Sickle Cell/genetics Haematopoiesis beta-Globins/genetics 030104 developmental biology PROGENITOR CELLS 030220 oncology & carcinogenesis Cancer research CRISPR-Cas Systems Stem cell MIXED CHIMERISM business Ex vivo |
| Zdroj: | Sci Transl Med Lattanzi, A, Camarena, J, Lahiri, P, Segal, H, Srifa, W, Vakulskas, C A, Frock, R L, Kenrick, J, Lee, C, Talbott, N, Skowronski, J, Cromer, M K, Charlesworth, C T, Bak, R O, Mantri, S, Bao, G, DiGiusto, D, Tisdale, J, Wright, J F, Bhatia, N, Roncarolo, M G, Dever, D P & Porteus, M H 2021, ' Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease ', Science Translational Medicine, vol. 13, no. 598, eabf2444 . https://doi.org/10.1126/scitranslmed.abf2444 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | Sickle cell disease (SCD) is the most common monogenic serious disease with 300,000 births annually worldwide. SCD is autosomal recessive from a single point mutation in codon six of the β-globin gene (HBB) resulting in sickle hemoglobin. Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) might be an ideal treatment of SCD. We previously developed an HBB gene targeting strategy that utilizes high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce rAAV6-mediated gene correction of the SCD-causing mutation in HSPCs. Here we present foundational translational data that demonstrate the pre-clinical feasibility, efficacy, and toxicology of HBB gene correction in plerixafor-mobilized CD34+ cells from healthy and SCD patient donors (Drug Product-gcHBB-SCD). Notably, we achieved up to 60% HBB allelic correction in clinical-scale gcHBB-SCD manufacturing and long-term engraftment in immunodeficient NSG mice, with multi-lineage allele gene correction frequencies of 20% in multiple hematopoietic organs. The long-term safety tumorigenicity/toxicology study demonstrated no evidence of abnormal hematopoiesis, genotoxicity or tumorigenicity from the engrafted gcHBB-SCD Drug Product. Altogether, this preclinical data supports the safety, efficacy, and reproducibility of a gene correction strategy for initiation of a Phase I/II clinical trial for SCD patients. |
| Databáze: | OpenAIRE |
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