Safety Profile of Gutless Adenovirus Vectors Delivered into the Normal Brain Parenchyma: Implications for a Glioma Phase 1 Clinical Trial
| Autor: | Kyle R. Kelson, Philip Ng, Robert N. Pechnick, Pedro R. Lowenstein, Kurt M. Kroeger, Weidong Xiong, Alireza Salem, A.K.M. Ghulam Muhammad, Chunyan Liu, Donna Palmer, Liliana M. Lacayo, Mariana Puntel, Maria G. Castro, Catherine Farrokhi |
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| Rok vydání: | 2012 |
| Předmět: |
Male
CIENCIAS MÉDICAS Y DE LA SALUD Genetic enhancement Transgene Genetic Vectors Ciencias de la Salud Herpesvirus 1 Human Biology medicine.disease_cause Thymidine Kinase Applied Microbiology and Biotechnology Article HSV-1TK & FLt3L Adenoviridae Transduction Genetic preclinical study Glioma Genetics medicine Animals Humans Tissue Distribution Vector (molecular biology) Genetics (clinical) Pharmacology Behavior Animal Clinical Trials Phase I as Topic Brain medicine.disease Rats HC-Ad Otras Ciencias de la Salud Disease Models Animal GLioblastoma fms-Like Tyrosine Kinase 3 Rats Inbred Lew Thymidine kinase Fms-Like Tyrosine Kinase 3 Immunology Toxicity Cancer research Molecular Medicine Blood Chemical Analysis |
| Zdroj: | Human Gene Therapy Methods. 23:271-284 |
| ISSN: | 1946-6544 1946-6536 |
| Popis: | Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10 8, 1×109, and 1×1010 viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×109 VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads. Fil: Ghulam Muhammad, A.K.M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos Fil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos Fil: Puntel, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos Fil: Farrokhi, Catherine. Cedars Sinai Medical Center; Estados Unidos Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos Fil: Salem, Alireza. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos Fil: Lacayo, Liliana. Cedars Sinai Medical Center; Estados Unidos Fil: Pechnick, Robert N.. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles; Estados Unidos Fil: Kelson, Kyle R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos Fil: Palmer, Donna. Baylor College of Medicine; Estados Unidos Fil: Ng, Philip. Baylor College of Medicine; Estados Unidos Fil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos Fil: Castro, Maria G.. University of Michigan; Estados Unidos. University of California at Los Angeles; Estados Unidos. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos |
| Databáze: | OpenAIRE |
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