A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors

Richard Pyles, Ronald E. Warnick, Claudia L. Chalk, Bridget E. Szanti, Linda M. Parysek

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

A promising approach for the therapeutic treatment of brain tumors utilizes replication-competent, neuroattenuated herpes simplex virus-1 (HSV-1) mutants. This approach requires mutation of HSV-1 to eliminate killing of normal, nondividing cells of the brain (e.g., neurons). We have generated a HSV-1 double-mutant, designated 3616UB, by interrupting the uracil DNA glycosylase (UNG) gene in a previously studied ICP34.5 mutant, R3616, The HSV-1-encoded UNG gene is required for efficient HSV-1 replication in nondividing cells, but is dispensable for replication in rapidly dividing cells. The specific function of the HSV-1 ICP34.5 gene is not completely clear, but it is thought to be necessary for viral replication in cells of the nervous system, because, when mutated, the resultant viral strains are fully neuroattenuated. Strain 3616UB did not replicate in primary neuronal cultures in vitro or in mouse brain, but efficiently killed six of six human tumor cell lines within 6 days in vitro and successfully infected and replicated within brain tumor xenografts. The potential safety of 3616UB for human use is enhanced by an unexpected hypersensitivity to the antiherpetic drug ganciclovir. These data suggest that 3616UB may be effective for the treatment of human brain tumors. Intratumoral injection of 3616UB into human medulloblastoma or angiosarcoma xenografts established in severe combined immunodeficient (SCID) mice produced significant growth arrest and some tumor regressions. Strain 3616UB was as effective as R3616 in this therapy study and did not cause any obvious distress in the treated animals. Together, the data show that 3616UB is a very safe alternative to other HSV-1 mutants because the presence of two mutations reduces the possibility of recombinational events in situ that could lead to the generation of virulent viral progeny during 3616UB therapy.

Original languageEnglish (US)
Pages (from-to)533-544
Number of pages12
JournalHuman Gene Therapy
Volume8
Issue number5
StatePublished - Mar 20 1997
Externally publishedYes

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Human Herpesvirus 1
Brain Neoplasms
HhAntag691
Uracil-DNA Glycosidase
Heterografts
Therapeutics
Genes
Mutation
Hemangiosarcoma
Medulloblastoma
Ganciclovir
SCID Mice
Brain
Virus Replication
Tumor Cell Line
Nervous System
Hypersensitivity
Safety
Neurons
Injections

ASJC Scopus subject areas

  • Genetics

Cite this

Pyles, R., Warnick, R. E., Chalk, C. L., Szanti, B. E., & Parysek, L. M. (1997). A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors. Human Gene Therapy, 8(5), 533-544.

A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors. / Pyles, Richard; Warnick, Ronald E.; Chalk, Claudia L.; Szanti, Bridget E.; Parysek, Linda M.

In: Human Gene Therapy, Vol. 8, No. 5, 20.03.1997, p. 533-544.

Research output: Contribution to journalArticle

Pyles, R, Warnick, RE, Chalk, CL, Szanti, BE & Parysek, LM 1997, 'A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors', Human Gene Therapy, vol. 8, no. 5, pp. 533-544.
Pyles R, Warnick RE, Chalk CL, Szanti BE, Parysek LM. A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors. Human Gene Therapy. 1997 Mar 20;8(5):533-544.
Pyles, Richard ; Warnick, Ronald E. ; Chalk, Claudia L. ; Szanti, Bridget E. ; Parysek, Linda M. / A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors. In: Human Gene Therapy. 1997 ; Vol. 8, No. 5. pp. 533-544.
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