Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Off-target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99% in murine (J774A.1) macrophages and by 50% in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 min post virus administration. Circulating virus was still detectable 30 min post infusion in mice pre-dosed with poly(I) whereas no detectable MV was found at 5-10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.

Original languageEnglish (US)
Pages (from-to)202-211
Number of pages10
JournalCancer Gene Therapy
Volume19
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Poly I
Measles virus
Scavenger Receptors
Kupffer Cells
Viruses
Therapeutics
Macrophages
Blood-Borne Pathogens
Oncolytic Viruses
Measles
Secondary Prevention
Heterografts
Spleen
Ligands
Gene Expression
Liver
Growth

Keywords

  • measles
  • mononuclear phagocytic system
  • poly(I)
  • sequestration

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

@article{9b183f5632fe419bb17bffb8a1020800,
title = "Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus",
abstract = "Off-target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99{\%} in murine (J774A.1) macrophages and by 50{\%} in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 min post virus administration. Circulating virus was still detectable 30 min post infusion in mice pre-dosed with poly(I) whereas no detectable MV was found at 5-10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.",
keywords = "measles, mononuclear phagocytic system, poly(I), sequestration",
author = "Liu, {Y. P.} and C. Tong and Angela Dispenzieri and Federspiel, {Mark J} and Russell, {Stephen J} and Kah-Whye Peng",
year = "2012",
month = "3",
doi = "10.1038/cgt.2011.82",
language = "English (US)",
volume = "19",
pages = "202--211",
journal = "Cancer Gene Therapy",
issn = "0929-1903",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus

AU - Liu, Y. P.

AU - Tong, C.

AU - Dispenzieri, Angela

AU - Federspiel, Mark J

AU - Russell, Stephen J

AU - Peng, Kah-Whye

PY - 2012/3

Y1 - 2012/3

N2 - Off-target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99% in murine (J774A.1) macrophages and by 50% in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 min post virus administration. Circulating virus was still detectable 30 min post infusion in mice pre-dosed with poly(I) whereas no detectable MV was found at 5-10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.

AB - Off-target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99% in murine (J774A.1) macrophages and by 50% in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 min post virus administration. Circulating virus was still detectable 30 min post infusion in mice pre-dosed with poly(I) whereas no detectable MV was found at 5-10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.

KW - measles

KW - mononuclear phagocytic system

KW - poly(I)

KW - sequestration

UR - http://www.scopus.com/inward/record.url?scp=84857110365&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857110365&partnerID=8YFLogxK

U2 - 10.1038/cgt.2011.82

DO - 10.1038/cgt.2011.82

M3 - Article

VL - 19

SP - 202

EP - 211

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 3

ER -