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 language | English |
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Pages (from-to) | 2100-112 |
Number of pages | 13 |
Journal | Journal of Clinical Investigation |
Volume | 119 |
Issue number | 7 |
Publication status | Published - 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