Distribution properties of lentiviral vectors administered into the striatum by convection-enhanced delivery

Edward White, Ali S Bienemann, Lisa Megraw, Chotirote Bunnun, Marcella Wyatt, Hannah Taylor, Steven Gill

Research output: Contribution to journalArticle (Academic Journal)

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)115-27
Number of pages13
JournalHuman Gene Therapy
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 2012

Keywords

  • Animals
  • Convection
  • Corpus Striatum
  • Gene Transfer Techniques
  • Genes, Reporter
  • Genetic Vectors
  • HIV
  • Heparin
  • Infectious Anemia Virus, Equine
  • Lentivirus
  • Magnetic Resonance Imaging
  • Male
  • Membrane Glycoproteins
  • Microscopy, Confocal
  • Nimodipine
  • Rats
  • Rats, Wistar
  • Swine
  • Vesicular stomatitis Indiana virus
  • Viral Envelope Proteins
  • beta-Galactosidase

Fingerprint Dive into the research topics of 'Distribution properties of lentiviral vectors administered into the striatum by convection-enhanced delivery'. Together they form a unique fingerprint.

Cite this