Adeno-associated viral-mediated insulin-like growth factor delivery protects motor neurons in vitro.
Recent work has demonstrated that adeno-associated viral (AAV) vector-mediated delivery of the insulin-like growth factor (IGF-I) gene through retrograde axonal transport can prolong survival and delay disease onset in the superoxide dismutase mutant mouse model of motor neuron (MN) disease. The present experiment examines IGF-I gene transfer in vitro. Adenoviral and AAV vectors for IGF-I infect neurons triggering expression and secretion of biologically active IGF-I. AAV-mediated IGF-I expression in SH-SY5Y neurons protects both cells expressing the transgene, and bystanders without transgene expression from glutamate-induced apoptosis. Similarly, AAV-mediated IGF-I delivery in primary E15 MN culture provides a titer-dependent neuroprotection from glutamate-induced DNA fragmentation. Both infected and noninfected neurons are equally protected. These observations argue that vector-mediated IGF-I gene transfer induces secretion of active IGF-I that acts through direct effects on spinal cord MNs. This mechanism may explain the therapeutic effects observed in vivo despite relatively low affinity AAV spinal cord uptake.
Vincent
Andrea M
AM
Department of Neurology, University of Michigan, MI, USA.
Feldman
Eva L
EL
Song
Debbie K
DK
Jung
Verena
V
Schild
Andreas
A
Zhang
Wei
W
Imperiale
Michael J
MJ
Boulis
Nicholas M
NM
D000818:Animals; D003001:Cloning, Molecular; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology*; D051381:Rats; D013116:Spinal Cord / Q000502:physiology*
D007334:Insulin-Like Growth Factor I