5019 Thurston Bowles
Lentiviral vector-based Gene therapy
Lentiviral vectors efficiently ferry large genetic cargos to dividing and non-dividing cells in vitro and in vivo. Integration of the vector genome into host cell chromatin is the hallmark of lentiviral vectors, which bestows vector genome persistency in proliferating cells and thus renders lentiviral vectors ideal for human gene therapy applications. This notion has been strongly supported by recent successes in correcting human genetic diseases, and curing patients with hematologic and solid tumors. The need to utilize the capabilities offered by lentiviral vectors and yet to avoid the risks of insertional mutagenesis was the initial drive for the development of integration deficient lentiviral vector (IDLV) systems. In addition the rapid clearance of episomal-IDLV genomes in proliferating cells renders IDLV’s highly suitable for recently emerging research and clinical applications premised on transient transgene expression, including immunotherapy, gene vaccination, and genome editing (using the CRISPR and the zinc-finger nucleases technologies). Our laboratory has been focused on overcoming major impediments inherent to episomal viral vectors. These include: epigenetic silencing of episomal vectors, illegitimate integrase-independent integration, and the lack of IDLV stable packaging cell lines (see selected publications).
In addition we are interested in developing precision gene therapy approach, to this end our laboratory is focused on studying the effects of the host genetic background on the efficacy and safety of lentiviral vector gene delivery (see selected publication.
Finally, we recently initiated a new NIH funded study aimed at characterizing the effects of the circadian rhythm on in vivo and in vitro gene delivery by viral vectors.
Hu et.al. Superior lentiviral vectors designed for BSL-0 environment abolish vector mobilization. Gene Ther. 2018 Oct;25(7):454-472
Suwanmanee et.al. Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery. Mol Ther Methods Clin Dev. 2017 Jun 16;5:83-92
Hu et.al . Generation of a stable packaging cell line producing high-titer PPT-deleted integration-deficient lentiviral vectors. Mol Ther Methods Clin Dev. 2015;2:15025.
Cockrell et.al. The HIV-1 Rev/RRE system is required for HIV-1 5′ UTR cis elements to augment encapsidation of heterologous RNA into HIV-1 viral particles. Retrovirology. 2011 Jun 24;8:51. doi: 10.1186/1742-4690-8-51
Kantor et.al. Notable reduction in illegitimate integration mediated by a PPT-deleted, nonintegrating lentiviral vector. Mol Ther. 2011 Mar;19(3):547-56.
Kantor et.al. Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18786-91