DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice.
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.
Terashima
Tomoya
T
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Oka
Kazuhiro
K
Kritz
Angelika B
AB
Kojima
Hideto
H
Baker
Andrew H
AH
Chan
Lawrence
L
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012497:Sandhoff Disease / Q000628:therapy*; D019076:Transgenes; D054821:beta-Hexosaminidase beta Chain / Q000235:genetics*
C045073:Cre recombinase; D019426:Integrases; D054821:beta-Hexosaminidase beta Chain