Murine retroviral vectors can infect a wide variety of proliferating mammalian cell types (e.g. lymphocytes). Non-proliferating tissues (e.g. neurons) are not transduced by murine retroviral vectors. These findings suggest that this type of vector may be useful for the selective introduction of genes into growing tumors in the brain, since the tumor is essentially the only tissue that will integrate and express the vector genes.
To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery.
Although it has been established that the left cerebral hemisphere subserves spoken language, the nature of brain organization for sign language remains relatively unexplored. The issue is especially important because sign language displays the complex linguistic structure of spoken languages, but conveys it through manipulation of visuo-spatial relations, thereby exhibiting properties for which the hemispheres of hearing individuals show opposing specializations. We had the unique opportunity to study a hearing signer proficient in American sign language (ASL), during the left intracarotid injection of a barbiturate (the Wada test), and before and after a right temporal lobectomy. The subject was a strong right-hander. Neuropsychological and anatomical asymmetries suggested left cerebral dominance for auditory-based language. Emission tomography revealed lateralized activity of left Broca's and Wernicke's regions for spoken language. The Wada test, during which all left language areas were rendered inoperative, caused a marked aphasia in both English and ASL. After partial ablation of the right temporal lobe, the abilities to sign and understand signing were unchanged. These data add further support to the notion that anatomical structures of the left cerebral hemisphere subserve language in a visuo-spatial as well as an auditory mode.
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