title: Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: implications for a glioma phase 1 clinical trial.
abstract: 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), 1×10(9), and 1×10(10) 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 1×10(9) 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.
authors.affiliation: Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: A K M Ghulam
authors.initials: AK
authors.lastname: Muhammad
authors.forename: Weidong
authors.initials: W
authors.lastname: Xiong
authors.forename: Mariana
authors.initials: M
authors.lastname: Puntel
authors.forename: Catherine
authors.initials: C
authors.lastname: Farrokhi
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Kroeger
authors.forename: Alireza
authors.initials: A
authors.lastname: Salem
authors.forename: Liliana
authors.initials: L
authors.lastname: Lacayo
authors.forename: Robert N
authors.initials: RN
authors.lastname: Pechnick
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Kelson
authors.forename: Donna
authors.initials: D
authors.lastname: Palmer
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001774:Blood Chemical Analysis; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D005910:Glioma / Q000628:therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013937:Thymidine Kinase / Q000235:genetics; D014018:Tissue Distribution; D014161:Transduction, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D013937:Thymidine Kinase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3