Efficient retrograde transport of adeno-associated virus type 8 to spinal cord and dorsal root ganglion after vector delivery in muscle.
The peripheral nervous system (PNS), including peripheral nerves and dorsal root ganglion (DRG), is involved in numerous neurological disorders, such as peripheral neuropathies (diabetic neuropathy, chronic pain, etc.) and demyelination diseases (multiple sclerosis, congenital muscular dystrophy, Charcot-Marie-Tooth disease, etc.). Effective clinical interventions for those diseases are very limited. Gene therapy represents a novel therapeutic strategy for the PNS diseases, especially with simply and minimally invasive delivery methods. Previously, we have shown that adeno-associated virus type 8 (AAV8) can efficiently transduce muscles body wide by a simple intraperitoneal injection in neonatal mice. In this study, we investigated the capacity of AAV8 in transducing PNS in neonatal mice by intraperitoneal injection and also in adult mice by intramuscular injection. Efficient and long-term gene transfer was found in the white matter of the spinal cord, DRG neurons, and peripheral nerves in both groups, treated either as neonates or as adults, particularly neonates. In the adult mice injected with AAV8 in tibialis anterior and gastrocnemius muscles in one of the hind legs, more neurons were transduced in the lower part of the spinal cord than in the upper part; the DRG neurons were transduced more on the vector-injected side than in the contralateral uninjected side. Few cells in the gray matter of the spinal cord were transduced regardless of the delivery methods and age of the mice. These results support the mechanism of vector retrograde transport and suggest that AAV8 crosses blood-nerve barrier poorly. Our finding should have important implications in gene therapy for peripheral neurological disorders.
Zheng
Hui
H
Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University , Sun Yat-sen University, Guangzhou 510080, China.
Qiao
Chunping
C
Wang
Chi-Hsien
CH
Li
Juan
J
Li
Jianbin
J
Yuan
Zhenhua
Z
Zhang
Cheng
C
Xiao
Xiao
X
D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport; D000229:Dependovirus / Q000145:classification / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000166:cytology / Q000821:virology*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000378:metabolism*; D007273:Injections, Intramuscular; D051379:Mice; D009132:Muscles / Q000821:virology*; D009474:Neurons / Q000166:cytology / Q000821:virology; D012703:Serotyping; D013116:Spinal Cord / Q000166:cytology / Q000821:virology*; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000378:metabolism
D001616:beta-Galactosidase