Advanced Central Nervous System (CNS) MalignancyThe clinical trial for patients with advanced gliomas (glioblastoma multiforme and anaplastic astrocytomas) began enrolling patients last Spring [1996] and subsequently treated three patients in one arm of the trial. These patients all underwent stereotactic injection of 108 pfu adenovirus expressing herpes virus thymidine kinase (Ad.HSVtk) followed by systemic ganciclovir for one week and then tumor resection. The residual, unresectable, portion of the tumor was treated with same dose of virus and an additional two weeks of ganciclovir.All of the patients tolerated the therapy well and experienced little or no direct toxicity from the virus. This trial is continuing with additional patients to be enrolled at higher doses for the same treatment, as well as patients being enrolled to a second arm of the trial which will only provide stereotactic treatment of the tumor without resection. A similar trial has recently begun at Baylor College under the direction of Drs. Grossman and Shine. Other trials are also planned in the Netherlands and at Mt. Sinai Hospital in New York. The University of Pennsylvania trial is the most comprehensive clinical trial in that patients will be studied in two distinct clinical settings (with and without tumor resection). The resected tumor provides important histopathologic data, whereas the unresected group has the potential to demonstrate tumor regression. See also:
MesotheliomaThe phase I clinical trial on the use of gene transfer in mesothelioma has been completed. A total of 15 patients were enrolled, each of which received an adenovirus expressing herpes virus thymidine kinase (Ad.HSVtk) into the plural space followed by treatment with ganciclovir. The patients tolerated high dose vector extremely well. The team is currently analyzing the results of this study with respect to efficiency of gene transfer and immunologic responses to the vector. Plans for extending this study are currently underway.Cystic FibrosisThe phase I clinical trial for the treatment of cystic fibrosis with adenoviral vectors has been restarted with the introduction of a third generation adenoviral vector. The vector of choice that emerged following extensive experiments in the laboratory is based on human adenovirus 5 with complete deletions in E1 and E4. This construct elicits far less immunity and is substantially safer when evaluated in multiple rodents and non-human primate settings. Patients receive a signal dose of adenoviral vector through a bronchoscope into a segment of lung and are evaluated for efficiency of gene expression with follow-up brochoscopies on day 4 and 42 after gene transfer.For more information, see:
Gene Therapy for Cystic Fibrosis (CF)
Ornithine Transcarbamylase DeficiencyA new clinical trial was recently approved for the introduction of adenoviral vectors into the liver of female carriers of the metabolic disorder ornithine transcarbamylase deficiency. This disease primarily afflicts male infants who develop life threatening hyperammonemic coma within the first few days of life.The gene that is defective in this disease (ornithine transcarbamylase) is expressed in liver, an organ which is efficiently targeted with adenoviral vectors through systemic injection of the vector. Experiments in a murine model showed efficacy and safety of the adenoviral vector while studies in rodents and non-human primates confirmed the safety of the experiment. The patient will be evaluated for evidence of gene expression through indirect metabolic measurements as well as a single liver biopsy. The first patients should be enrolled in this first trial by January 1997. For more information, see:
Gene Therapy for Ornithine Transcarbamylase (OTC) deficiency
|
