Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates

S. J. Gray, S. Nagabhushan Kalburgi, T. J. McCown, R. Jude Samulski

Research output: Contribution to journalArticle

158 Scopus citations

Abstract

Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 10 12 vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases.

Original languageEnglish (US)
Pages (from-to)450-459
Number of pages10
JournalGene Therapy
Volume20
Issue number4
DOIs
StatePublished - Apr 1 2013

Keywords

  • AAV
  • brain
  • cerebrospinal fluid
  • non-human primate
  • spinal cord

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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