Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of intrathecal, retroviral-mediated transfer of the herpes simplex thymidine kinase (HStk) gene and subsequent ganciclovir (GCV) administration has recently been shown to improve survival in a rat model of leptomeningeal carcinomatosis. Clinical application of this approach is attractive because access to the cerebrospinal fluid (CSF) space is relatively noninvasive and distribution of producer cells and vectors may be facilitated by circulation of CSF, overcoming distribution problems inherent in solid tumors. However, meningeal inflammation, transduction and injury to normal CNS tissue, proliferation of the xenogeneic producer cells in the subarachnoid space, immune-mediated injury, and development of hydrocephalus are possible complications of intraventricular or intrathecal administration of vector-producer cells. In addition, the dynamics of producer cell and vector distribution in the CSF are unknown. To address these issues, we evaluated the safety of this approach for gene delivery and assessed the dynamics of distribution of producer cells and retroviral vectors in rats and non-human primates. In rats, transduction of normal central nervous system (CNS) structures surrounding the subarachnoid space was evaluated after intrathecal and intraventricular injections of beta-galactosidase and HStk vector-producer cells, with and without GCV. In primates, beta-galactosidase and HStk vector-producer cells were injected intraventricularly and GCV was administered either intrathecally or intravenously. Toxicity was evaluated by neurologic examination, serial gadolinium-enhanced MRI scans of the brain, and blood and CSF profiles. A subgroup of monkeys received repeated intraventricular injection of vector-producer cells and intravenous GCV. The titer of retroviral-vector was measured in cisternal and lumbar CSF samples after repeated producer cell injection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells. 762 Dec 61

Leptomeningeal carcinomatosis is a painful and debilitating complication of cancer. Indwelling reservoirs provide continuous assess to the subarachnoid space, making leptomeningeal cancer potentially amenable to gene therapy. Adeno-associated virus (AAV) is a defective virus not associated with any human disease. We used an AAV vector to transduce medulloblastoma (DAOY) cells in a nude rat model of leptomeningeal disease. After intraventricular injection of vector carrying the bacterial lacZ gene, beta-galactosidase positive cells were found in the implanted tumor and in ependymal and subependymal cells but not in underlying normal brain parenchyma. No evidence of virally-mediated toxicity was noted in the animals. The results of this pilot study demonstrate that AAV vectors may be used to transfer and express foreign genes in established leptomeningeal tumors.
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PMID:Adeno-associated viral vector gene transfer into leptomeningeal xenografts. 921 60