期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 13, 期 -, 页码 390-398出版社
CELL PRESS
DOI: 10.1016/j.omtm.2019.03.005
关键词
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资金
- California Institute for Regenerative Medicine [DR3-06945]
- UCLA Broad Stem Cell Research Center
- Whitcome Predoctoral Training Program at the UCLA Molecular Biology Institute
- T32 Medical Scientist Training Program at UCLA [T32GM008042]
Lentiviral vector (LV)-based hematopoietic stem and progenitor cell (HSPC) gene therapy is becoming a promising alternative to allogeneic stem cell transplantation for curing genetic diseases. Clinical trials are currently underway to treat sickle cell disease using LVs expressing designed anti-sickling globin genes. However, because of the large size and complexity of the human beta-globin gene, LV products often have low titers and transduction efficiency, requiring large amounts to treat a single patient. Furthermore, transduction of patient HSPCs often fails to achieve a sufficiently high vector copy number (VCN) and transgene expression for clinical benefit. We therefore investigated the combination of two compounds (PGE2 and poloxamer synperonic F108) to enhance transduction of HSPCs with a clinical-scale preparation of Lenti/G-AS3-FB. Here, we found that transduction enhancers increased the in vitro VCN of bulk myeloid cultures similar to 10-fold while using a 10-fold lower LV dose. This was accompanied by an increased percentage of transduced colony-forming units. Importantly, analysis of immune-deficient NSG xenografts revealed that the combination of PGE2/synperonic F108 increased LV gene transfer in a primitive HSC population, with no effects on lineage distribution or engraftment. The use of transduction enhancers may greatly improve efficacy for LV-based HSPC gene therapy.
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