DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice

Tomoya Terashima, Kazuhiro Oka, Angelika B Kritz, Hideto Kojima, Andrew H Baker, Lawrence Chan

Research output: Contribution to journalArticlepeer-review

Abstract

Dorsal root ganglion (DRG) neuron dysfunction occurs in a variety of sensory neuronopathies for which there are currently no satisfactory treatments. Here we describe the development of a strategy to target therapeutic genes to DRG neurons for the treatment of these disorders. We genetically modified an adenovirus (Ad) to generate a helper virus (HV) that was detargeted for native adenoviral tropism and contained DRG homing peptides in the adenoviral capsid fiber protein; we used this HV to generate DRG-targeted helper-dependent Ad (HDAd). In mice, intrathecal injection of this HDAd produced a 100-fold higher transduction of DRG neurons and a markedly attenuated inflammatory response compared with unmodified HDAd. We also injected HDAd encoding the beta subunit of beta-hexosaminidase (Hexb) into Hexb-deficient mice, a model of the neuronopathy Sandhoff disease. Delivery of the DRG-targeted HDAd reinstated neuron-specific Hexb production, reversed gangliosidosis, and ameliorated peripheral sensory dysfunction. The development of DRG neuron-targeted HDAd with proven efficacy in a preclinical model may have implications for the treatment of sensory neuronopathies of diverse etiologies.

Original languageEnglish
Pages (from-to)2100-112
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number7
Publication statusPublished - Jul 2009

Keywords

  • Adenoviridae
  • Animals
  • Cells, Cultured
  • Ganglia, Spinal
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Integrases
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Sandhoff Disease
  • Transgenes
  • beta-Hexosaminidase beta Chain

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