A Novel Bicistronic High-Capacity Gutless Adenovirus Vector That Drives Constitutive Expression of Herpes Simplex Virus Type 1 Thymidine Kinase and Tet-Inducible Expression of Flt3L for Glioma Therapeutics

被引：38

作者：

Puntel, Mariana ^{[1
]}

Muhammad, A. K. M. G. ^{[1
]}

Candolfi, Marianela ^{[1
]}

Salem, Alireza ^{[1
]}

Yagiz, Kader ^{[1
]}

Farrokhi, Catherine ^{[2
]}

Kroeger, Kurt M. ^{[1
]}

Xiong, Weidong ^{[1
]}

Curtin, James F. ^{[1
]}

Liu, Chunyan ^{[1
]}

Bondale, Niyati S. ^{[1
]}

Lerner, Jonathan ^{[1
]}

Pechnick, Robert N. ^{[2
,3
,4
]}

Palmer, Donna ^{[5
]}

Ng, Philip ^{[5
]}

Lowenstein, Pedro R. ^{[1
,4
,6
,7
,8
]}

Castro, Maria G. ^{[1
,4
,6
,7
,8
]}

机构：

[1] Cedars Sinai Med Ctr, Gene Therapeut Res Inst, Los Angeles, CA 90048 USA

[2] Cedars Sinai Med Ctr, Dept Psychiat & Behav Neurosci, Los Angeles, CA 90048 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Neurosci, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA

[5] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[6] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA

[7] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

来源：

JOURNAL OF VIROLOGY | 2010年 / 84卷 / 12期

基金：

美国国家卫生研究院;

关键词：

GLIOBLASTOMA-MULTIFORME PATIENTS; MEDIATED GENE-THERAPY; TRANSGENE EXPRESSION; MALIGNANT GLIOMA; IN-VIVO; BRAIN INFLAMMATION; CLINICAL-TRIALS; IMMUNE; CELLS; RESPONSES;

D O I：

10.1128/JVI.00398-10

中图分类号：

Q93 [微生物学];

学科分类号：

071005 [微生物学];

摘要：

Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Conditional cytotoxic/immune-stimulatory gene therapy (Ad-TK and Ad-Flt3L) elicits tumor regression and immunological memory in rodent GBM models. Since the majority of patients enrolled in clinical trials would exhibit adenovirus immunity, which could curtail transgene expression and therapeutic efficacy, we used high-capacity adenovirus vectors (HC-Ads) as a gene delivery platform. Herein, we describe for the first time a novel bicistronic HC-Ad driving constitutive expression of herpes simplex virus type 1 thymidine kinase (HSV1-TK) and inducible Tet-mediated expression of Flt3L within a single-vector platform. We achieved anti-GBM therapeutic efficacy with no overt toxicities using this bicistronic HC-Ad even in the presence of systemic Ad immunity. The bicistronic HC-Ad-TK/TetOn-Flt3L was delivered into intracranial gliomas in rats. Survival, vector biodistribution, neuropathology, systemic toxicity, and neurobehavioral deficits were assessed for up to 1 year posttreatment. Therapeutic efficacy was also assessed in animals preimmunized against Ads. We demonstrate therapeutic efficacy, with vector genomes being restricted to the brain injection site and an absence of overt toxicities. Importantly, antiadenoviral immunity did not inhibit therapeutic efficacy. These data represent the first report of a bicistronic vector platform driving the expression of two therapeutic transgenes, i.e., constitutive HSV1-TK and inducible Flt3L genes. Further, our data demonstrate no promoter interference and optimum gene delivery and expression from within this single-vector platform. Analysis of the efficacy, safety, and toxicity of this bicistronic HC-Ad vector in an animal model of GBM strongly supports further preclinical testing and downstream process development of HC-Ad-TK/TetOn-Flt3L for a future phase I clinical trial for GBM.

引用

页码：6007 / 6017

页数：11

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