Novel mutations in U L 24 and gH rescue efficient infection of an HSV vector retargeted to TrkA.

Autor: Marzulli M; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Hall BL; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Zhang M; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Goins WF; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Cohen JB; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Glorioso JC; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
Jazyk: angličtina
Zdroj: Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2023 Jul 03; Vol. 30, pp. 208-220. Date of Electronic Publication: 2023 Jul 03 (Print Publication: 2023).
DOI: 10.1016/j.omtm.2023.06.012
Abstrakt: Transductional targeting of herpes simplex virus (HSV)-based gene therapy vectors offers the potential for improved tissue-specific delivery and can be achieved by modification of the viral entry machinery to incorporate ligands that bind the desired cell surface proteins. The interaction of nerve growth factor (NGF) with tropomyosin receptor kinase A (TrkA) is essential for survival of sensory neurons during development and is involved in chronic pain signaling. We targeted HSV infection to TrkA-bearing cells by replacing the signal peptide and HVEM binding domain of glycoprotein D (gD) with pre-pro-NGF. This TrkA-targeted virus (KNGF) infected cells via both nectin-1 and TrkA. However, infection through TrkA was inefficient, prompting a genetic search for KNGF mutants showing enhanced infection following repeat passage on TrkA-expressing cells. These studies revealed unique point mutations in envelope glycoprotein gH and in U L 24, a factor absent from mature particles. Together these mutations rescued efficient infection of TrkA-expressing cells, including neurons, and facilitated the production of a completely retargeted KNGF derivative. These studies provide insight into HSV vector improvements that will allow production of replication-defective TrkA-targeted HSV for delivery to the peripheral nervous system and may be applied to other retargeted vector studies in the central nervous system.
Competing Interests: J.B.C. and J.C.G. are inventors of intellectual property licensed to Oncorus, Inc. (Cambridge, MA). J.C.G. is a consultant and Chair of the Scientific Advisory Board of Oncorus, Inc.
(© 2023 The Authors.)
Databáze: MEDLINE
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