ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 13 citations in OpenAlex.
- Nanocarrier-Based Gene Delivery Systems: Mechanisms, Clinical Translation, and Future Perspectives.Biotechnology and bioengineering · 2026Review
- Article
- Emerging Therapies for Sickle Cell Disease: From Symptom Management to Curative Gene Therapy.Cureus · 2025Review
- Sickle cell disease: understanding pathophysiology, clinical features and advances in gene therapy approaches.Frontiers in pharmacology · 2025Review
- CRISPR technology in human diseases.MedComm · 2024Review
- Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies.Molecular therapy. Nucleic acids · 2023Article
- Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies.Molecular therapy. Nucleic acids · 2023Article
- Combined approaches for increasing fetal hemoglobin (HbF) andFrontiers in genome editing · 2023Review
- Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat β-hemoglobinopathies.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
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Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sickle cell disease (SCD) is caused by a mutation in the β-globin gene leading to polymerization of the sickle hemoglobin (HbS) and deformation of red blood cells. Autologous transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically modified using lentiviral vectors (LVs) to express an anti-sickling β-globin leads to some clinical benefit in SCD patients, but it requires high-level transgene expression (i.e., high vector copy number [VCN]) to counteract HbS polymerization. Here, we developed therapeutic approaches combining LV-based gene addition and CRISPR-Cas9 strategies aimed to either knock down the sickle β-globin and increase the incorporation of an anti-sickling globin (AS3) in hemoglobin tetramers, or to induce the expression of anti-sickling fetal γ-globins. HSPCs from SCD patients were transduced with LVs expressing AS3 and a guide RNA either targeting the endogenous β-globin gene or regions involved in fetal hemoglobin silencing. Transfection of transduced cells with Cas9 protein resulted in high editing efficiency, elevated levels of anti-sickling hemoglobins, and rescue of the SCD phenotype at a significantly lower VCN compared to the conventional LV-based approach. This versatile platform can improve the efficacy of current gene addition approaches by combining different therapeutic strategies, thus reducing the vector amount required to achieve a therapeutic VCN and the associated genotoxicity risk.
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