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In this study we have investigated the pharmacokinetics and tissue distribution of GX-12, a multiple plasmid DNA vaccine for the treatment of HIV-1 infection. Plasmid DNA was rapidly degraded in blood with a half-life of 1.34 min and was no longer detectable at 90 min after intravenous injection in mice. After intramuscular injection, plasmid DNA concentration in the injection site rapidly declined to less than 1% of the initial concentration by 90 min post-injection. However, sub-picogram levels (per mg tissue) were occasionally detected for several days after injection. The relative proportions of the individual plasmids of GX-12 remained relatively constant at the injection site until 90 min post-injection. The concentration of plasmid DNA in tissues other than the injection site peaked at 90 min post-injection and decreased to undetectable levels at 8 h post-injection. The rapid in vivo degradation of GX-12 and absence of persistence in non-target tissues suggest that the risk of potential gene-related toxicities by GX-12 administration, such as expression in non-target tissues, insertional mutagenesis and germline transmission, is minimal.

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.

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