Generation of an Oncolytic Herpes Simplex Viral Vector Completely Retargeted to the GDNF Receptor GFRα1 for Specific Infection of Breast Cancer Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Nov 25

PMID 33233403

Citations 5

Authors

Bonnie L Hall

Daniela Leronni

Yoshitaka Miyagawa

William F Goins

Joseph C Glorioso

Justus B Cohen

Affiliations

Soon will be listed here.

Abstract

Oncolytic herpes simplex viruses (oHSV) are under development for the treatment of a variety of human cancers, including breast cancer, a leading cause of cancer mortality among women worldwide. Here we report the design of a fully retargeted oHSV for preferential infection of breast cancer cells through virus recognition of GFRα1, the cellular receptor for glial cell-derived neurotrophic factor (GDNF). GFRα1 displays a limited expression profile in normal adult tissue, but is upregulated in a subset of breast cancers. We generated a recombinant HSV expressing a completely retargeted glycoprotein D (gD), the viral attachment/entry protein, that incorporates pre-pro-GDNF in place of the signal peptide and HVEM binding domain of gD and contains a deletion of amino acid 38 to eliminate nectin-1 binding. We show that GFRα1 is necessary and sufficient for infection by the purified recombinant virus. Moreover, this virus enters and spreads in GFRα1-positive breast cancer cells in vitro and caused tumor regression upon intratumoral injection in vivo. Given the heterogeneity observed between and within individual breast cancers at the molecular level, these results expand our ability to deliver oHSV to specific tumors and suggest opportunities to enhance drug or viral treatments aimed at other receptors.

Citing Articles

Oncolytic herpes simplex viruses designed for targeted treatment of EGFR-bearing tumors.

Ingusci S, Hall B, Cohen J, Glorioso J Mol Ther Oncol. 2024; 32(1):200761.

PMID: 38596286 PMC: 10869753. DOI: 10.1016/j.omton.2024.200761.

Novel mutations in U24 and gH rescue efficient infection of an HSV vector retargeted to TrkA.

Marzulli M, Hall B, Zhang M, Goins W, Cohen J, Glorioso J Mol Ther Methods Clin Dev. 2023; 30:208-220.

PMID: 37519407 PMC: 10384243. DOI: 10.1016/j.omtm.2023.06.012.

Viruses as tools in gene therapy, vaccine development, and cancer treatment.

Umair M, Akusa F, Kashif H, Seerat-E-Fatima , Butt F, Azhar M Arch Virol. 2022; 167(6):1387-1404.

PMID: 35462594 PMC: 9035288. DOI: 10.1007/s00705-022-05432-8.

Immunotherapeutic Efficacy of Retargeted oHSVs Designed for Propagation in an Ad Hoc Cell Line.

Vannini A, Leoni V, Sanapo M, Gianni T, Giordani G, Gatta V Cancers (Basel). 2021; 13(2).

PMID: 33445744 PMC: 7828196. DOI: 10.3390/cancers13020266.

Generation of a Novel Mesothelin-Targeted Oncolytic Virus and Implemented Strategies for Manufacturing.

Froechlich G, Gentile C, Infante L, Caiazza C, Pagano P, Scatigna S Int J Mol Sci. 2021; 22(2).

PMID: 33418877 PMC: 7825047. DOI: 10.3390/ijms22020477.

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