title: Distribution properties of lentiviral vectors administered into the striatum by convection-enhanced delivery.
abstract: Before the successful use of lentiviral vectors in clinical trials it is essential that strategies for direct vector delivery into the brain be evaluated in vivo, particularly as these vectors are significantly larger than the brain extracellular space. To date no such studies have been undertaken. In this study, convection-enhanced delivery (CED) was employed in an attempt to achieve widespread lentiviral delivery in the striatum. Infusions of equine infectious anemia virus (EIAV) and HIV vector constructs expressing the reporter gene β-galactosidase (β-Gal) were undertaken into the striatum at a range of flow rates and viral titers. In rats, all EIAV and HIV infusions led to the extensive transduction of cells in perivascular spaces throughout the brain. Although infusions were performed under standardized conditions, the number and volume of distribution of transduced cells were highly variable, with approximately one-third of EIAV infusions leading to no concentrated cell transduction in the striatum. Heparin coinfusion had no effect on EIAV distribution, although coinfusion of nimodipine resulted in a significant reduction in the number and volume of distribution of transduced cells. Intrastriatal EIAV delivery in pigs led to extensive transduction of mainly neurons, which could be effectively visualized in real time by T(2)-weighted magnetic resonance imaging. No infusions were associated with a significant inflammatory response. Therefore, despite its large size, lentiviral vectors can be administered by CED to the striatum in both small and large animal models. However, the variability in vector distribution under standardized conditions and widespread vector distribution through the perivascular spaces raise serious concerns regarding the practicality of lentivirus-mediated gene therapy in the brain in clinical practice.
authors.affiliation: Department of Neurosurgery, Frenchay Hospital , Bristol BS16 1LE, United Kingdom.
authors.forename: Edward
authors.initials: E
authors.lastname: White
authors.forename: Alison
authors.initials: A
authors.lastname: Bienemann
authors.forename: Lisa
authors.initials: L
authors.lastname: Megraw
authors.forename: Chotirote
authors.initials: C
authors.lastname: Bunnun
authors.forename: Marcella
authors.initials: M
authors.lastname: Wyatt
authors.forename: Hannah
authors.initials: H
authors.lastname: Taylor
authors.forename: Steven
authors.initials: S
authors.lastname: Gill
mesh_terms: D000818:Animals; D018481:Convection; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D006678:HIV / Q000235:genetics; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology; D004860:Infectious Anemia Virus, Equine / Q000235:genetics; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D009553:Nimodipine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D009553:Nimodipine; D006493:Heparin; D001616:beta-Galactosidase