DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice
Tomoya Terashima, … , Andrew H. Baker, Lawrence Chan
Tomoya Terashima, … , Andrew H. Baker, Lawrence Chan
Published June 15, 2009
Citation Information: J Clin Invest. 2009;119(7):2100-2112. https://doi.org/10.1172/JCI39038.
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Technical Advance Genetics

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

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 β subunit of β-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.

Authors

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

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Figure 6

DRG-targeted Hexb expression rescues sensory neuronal responses in Hexb–/– mice.

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DRG-targeted Hexb expression rescues sensory neuronal responses in Hexb–...
Electrophysiological studies and behavior tests were performed at 4 and 8 weeks after treatment. (A) SNCV was measured on sural nerve. (B) SNAP was recorded in proximal site after stimulation in the distal site at ankle joint. (C) First contact time. (D) Adhesive removal test. Data are expressed as mean ± SD. n = 8 (empty vector); 9 (WF-Hexb); 11 (DRG1-Hexb); 12 (wild type). (E) Nissl stain. (F) PAS stain with hematoxylin for nuclear stain. Enlarged views of boxed regions are shown below. Arrows indicate granular formations in neurons. Scale bars: 20 μm. *P < 0.01, **P < 0.05. #P < 0.01, ##P < 0.05 versus wild type.