title: Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy.
abstract: Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.
authors.affiliation: Biopharmaceutical Research Laboratories ofDong-A Pharmaceutical Co., Ltd.Kyunggi-Do, Korea.
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Kim
authors.forename: Soon Hye
authors.initials: SH
authors.lastname: Park
authors.forename: Moonsup
authors.initials: M
authors.lastname: Jeong
authors.forename: O Seo
authors.initials: OS
authors.lastname: Kwon
authors.forename: Hyounmie
authors.initials: H
authors.lastname: Doh
authors.forename: Su Hyung
authors.initials: SH
authors.lastname: Kang
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: Byong Moon
authors.initials: BM
authors.lastname: Kim
authors.forename: Dai Wu
authors.initials: DW
authors.lastname: Seol
authors.forename: Byung Gee
authors.initials: BG
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017321:Clinical Trials, Phase I as Topic; D004279:DNA, Viral / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization / Q000235:genetics; D051381:Rats; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000493:pharmacokinetics*
chemical_list: D004279:DNA, Viral; D053221:TNF-Related Apoptosis-Inducing Ligand