Exp Mol Med.  2011 Oct;43(10):580-586. 10.3858/emm.2011.43.10.065.

Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy

• Kim CY
• Park SH
• Jeong M
• Kwon OS
• Doh H
• Kang SH
• Robbins PD
• Kim BM
• Seol DW
• Kim BG

• KMID: 1123370
• DOI: http://doi.org/10.3858/emm.2011.43.10.065

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.

Keyword

gene therapy; glioma; pharmacokinetics; TNF-related apoptosis-inducing ligand

MeSH Terms

Adenoviridae/genetics
Animals
Blood-Brain Barrier
Brain/drug effects/*metabolism/pathology
Brain Neoplasms/genetics/metabolism/pathology/*therapy
Clinical Trials, Phase I as Topic
DNA, Viral/metabolism
Disease Models, Animal
Drug Delivery Systems
Drug Evaluation, Preclinical
*Gene Therapy
Glioma/genetics/metabolism/pathology/*therapy
Humans
Liver/drug effects/metabolism/pathology
Protein Multimerization/genetics
Rats
Spleen/drug effects/metabolism/pathology
TNF-Related Apoptosis-Inducing Ligand/genetics/*pharmacokinetics