Lentiviral Vector Development for Sickle Cell Disease
Gene therapy is a potential alternative to human leukocyte antigen (HLA)-matched allogeneic hematopoietic stem cell transplantation in the treatment of sickle cell disease (SCD). Lentiviral vectors (LVs)-based gene therapy raises hopes for curing SCD. With Ph.D. level scientists and extensive experience in LV development, Creative Biolabs is dedicated to meeting every unique need of our clients in LV development for SCD.
Introduction of SCD
SCD is caused by a mutation in the sixth amino acid of the hemoglobin (Hb) β-chain (E6V), affecting about 312,000 newborns worldwide annually. The mutation induces polymerization of Hb tetramers, red blood cell deformation, ischemia, anemia, and multiple organ damage. As a consequence, red blood cells (RBCs) lose flexibility and adopt the characteristic sickle shape in the capillary circulation. Additionally, sickled RBCs are prone to hemolysis, thus, the clinical phenotype is also characterized by hemolytic anemia.
Treatment of SCD
Current treatments of SCD include life-long RBC transfusions and hydroxyurea, a drug that increases fetal Hb synthesis. Indeed, the clinical course of SCD is improved when fetal HBG genes are highly expressed. However, pharmacological treatments increasing Hb levels are not equally effective in all patients. The only definitive cure for SCD patients is allogeneic hematopoietic stem cell (HSC) transplantation. However, HSC transplantation from an HLA-matched related donor is available only to a minority of patients. Transplantation of HSCs from matched unrelated donors is associated with a higher risk of graft-versus-host-disease, transplant rejection and infections.
Currently, with the advent of HBB expressing LVs, LV-based gene therapy holds the promise of avoiding the need for suitable donors and reducing the morbidity and mortality associated with allogeneic transplantation. LV-based gene therapy strategies require the stable transfer of an anti-sickling HBB globin transgene and sustained expression of the therapeutic globin chain. Several LVs have been developed and tested in murine models of SCD and patients' hematopoietic stem progenitor cells (HSPCs). Moreover, pre-clinical and clinical studies have shown the potential of LV-based gene therapy in correcting the SCD phenotype. The LVs used in these studies express either the fetal γ-globin or mutant β-globins that interfere with axial and lateral contacts in the HbS polymer, thereby reducing HbS polymerization and sickling.
Figure 1. Vector schematic: general organization of proviral form of lentiviral vectors for gene therapy for SCD. (Hoban, 2016)
LV Development for SCD at Creative Biolabs
Scientists at Creative Biolabs have developed several optimized LVs expressing the human β-AS3 gene under the control of a short promoter and a reduced version of the β-globin LCR. These vectors allow high transgene expression, which is essential for high-titer vector production. These optimized LVs can be potentially used in the clinical trials aimed at establishing the safety and efficacy of HSPCs transduced with LV for gene therapy for SCD.
Key Advantages of Our Service:
- Several optimized LVs expressing the human β-AS3 gene
- High-titer LVs, which are able to transduce a good proportion of HSCs
- A variety of tailored strategies for LV development
- Highly professional Ph.D. level scientists
Powered by our advanced platforms and experienced technical personnel, Creative Biolabs is fully competent to serve as your one-stop-shop for LV development for SCD. We offer turn-key or ala carte services customized to meet our client's needs. Please contact us for more information and a detailed quote.
Reference
- Hoban, M.D.; et al. (2016). Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood. 127(7):839-48.
