Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: implications for a glioma phase 1 clinical trial

MUHAMMAD; XIONG; PUNTEL; FAKHOURI; KROEGER; SALEM; LACAYO; PECHNICK; KELSON; PALMER; NG; LIU; LOWENSTEIN; CASTRO

Human Gene Therapy Methods

Mary Ann Liebert, Inc.

Año: 2012 vol. 23 p. 271 - 284

1946-6536

Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemicimmunity against the vectors can hamper therapeutic efficacy. We demonstrated that combinedimmunostimulation and cytotoxic gene therapy provides long-term survival in pre-clinicalglioma models. Since helper-dependent high capacity Ads (HC-Ads) elicit sustained transgeneexpression, in the presence of anti-adenoviral immunity, we engineered HC-Ads encodingconditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokinefms-like tyrosine kinase ligand 3 under the control of TetOn system. Escalating doses ofcombined HC-Ads (1x108, 1x109, 1x1010 vp) were delivered into the rat brain. We assessedneuropathology, biodistribution, transgene expression, systemic toxicity and behavioral impact atacute and chronic time points post-vector delivery. Histopathological analysis did not reveal anyevidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes wererestricted to the injection site. Serum chemistry did not uncover adverse systemic side effects atany of the doses tested. Taken together our data indicates that doses of up to 1x109 vp of eachHC-Ad can be safely administered into the normal brain. This comprehensive toxicity andbiodistribution study will lay the foundations for implementation of a Phase I clinical trial forGBM using HC-Ads.