Targeted retrograde gene delivery for neuronal protection.
The cellular heterogeneity and complex circuitry of the central nervous system make it difficult to achieve precise delivery of experimental and therapeutic agents. We report here an in vivo retrograde gene delivery strategy to target mature projection neurons using adeno-associated virus, a vector with low toxicity and the capacity for long-term gene expression. Viral delivery to axon terminal fields in the hippocampus and striatum resulted in viral internalization, retrograde transport, and transgene expression in specific projection neurons in entorhinal cortex and substantia nigra. Retrograde delivery of the anti-apoptotic gene Bcl2l (also known as Bcl-xL) protected entorhinal projection neurons from subsequent damage-induced cell death. Given the broad distribution of neurons affected by neurodegenerative diseases, gene delivery to both the terminal fields and the projection neurons through retrograde infection provides for strategic therapeutic intervention at both levels of the neural circuit. This approach may also facilitate experimental studies of defined neural circuits.
Kaspar
Brian K
BK
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Erickson
Dawn
D
Schaffer
David
D
Hinh
Linda
L
Gage
Fred H
FH
Peterson
Daniel A
DA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000378:metabolism; D017931:DNA Primers; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D017931:DNA Primers; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins