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.
View: Text | PDF
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

×

Figure 4

Fiber-modified HDAd supports long-term transgene expression and improves safety profile.

Options: View larger image (or click on image) Download as PowerPoint
Fiber-modified HDAd supports long-term transgene expression and improves...
(A) Long-term expression of lacZ gene in DRG. Ad or HDAd vectors (1 × 108 vp) were injected into C57BL/6 wild-type mice, and DRG was isolated at the indicated time points for quantitation of LacZ mRNA, normalized to β-actin mRNA. Results are expressed relative to day 5. (B–D) Targeted HDAd vector induces less inflammation. CSF was collected at the indicated time points, and cytokines IL-6 (B), TNF-α (C), and IL-1β (D) were measured by ELISA. *P < 0.01, **P < 0.05 versus HV-WF; #P < 0.01, ##P < 0.05 versus HDAd-WF-βgeo; ‡P < 0.001, †P < 0.01, ††P < 0.05 versus respective HV.