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- Title
DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice.
- Authors
Terashima, Tomoya; Oka, Kazuhiro; Kritz, Angelika B.; Kojima, Hideto; Baker, Andrew H.; Chan, Lawrence
- 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.
- Subjects
THORACIC vertebrae; PEPTIDES; LABORATORY mice; ETIOLOGY of diseases; NEURONS; ANIMAL experimentation; CELL culture; COMPARATIVE studies; ENZYMES; SENSORY ganglia; GENE therapy; GENES; GENETIC techniques; GLYCOSIDASES; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; RESEARCH funding; SPHINGOLIPIDOSES; VIRUSES; EVALUATION research
- Publication
Journal of Clinical Investigation, 2009, Vol 119, Issue 7, p2100
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI39038