Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells.
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)
Oshiro
E M
EM
Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Viola
J J
JJ
Oldfield
E H
EH
Walbridge
S
S
Bacher
J
J
Frank
J A
JA
Blaese
R M
RM
Ram
Z
Z
D016475:3T3 Cells / Q000637:transplantation*; D000818:Animals; D001927:Brain Diseases / Q000209:etiology; D002831:Choroid Plexus / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015774:Ganciclovir / Q000633:toxicity*; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D006085:Graft Survival; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008253:Macaca mulatta / Q000097:blood / Q000134:cerebrospinal fluid; D008279:Magnetic Resonance Imaging; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D051381:Rats / Q000097:blood / Q000134:cerebrospinal fluid; D011993:Recombinant Fusion Proteins / Q000378:metabolism* / Q000627:therapeutic use; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D013346:Subarachnoid Space; D013937:Thymidine Kinase / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D014018:Tissue Distribution; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D001616:beta-Galactosidase / Q000096:biosynthesis
D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir