Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain.
The ubiquitous expression of cell surface heparan sulfate proteoglycan, a binding receptor for adeno-associated virus type 2 (AAV-2), may account for the broad host range of this vector. Because the fibroblast growth factor receptor type 1 has been postulated to be a coreceptor for successful AAV-2 entry into host cells, we designed a strategy to investigate whether coadministration of this virus with basic fibroblast growth factor (bFGF) can enhance AAV-2-mediated gene delivery. We injected AAV-2-thymidine kinase (AAV-2-TK) vector into rat striata and checked whether coinjection with bFGF enhanced transduction and/or enlarged the area of transgene expression. Immunostaining confirmed the tropism of AAV-2-TK for neurons. The previous injection (7 days before vector delivery) of bFGF had no major impact on vector distribution area. However, when the vector was coinjected with bFGF, the right striatum showed an average viral transduction volume of 5 mm(3), which was more than 4-fold larger when compared with the left side (AAV-2-TK plus phosphate-buffered saline). This result clearly indicates that simultaneous injection of bFGF with AAV-2-TK can greatly enhance the volume of transduced tissue, probably by way of a competitive block of AAV-2-binding sites within the striatum. Robust TK immunoreactivity was also observed in the globus pallidus, which receives anterograde projections from the striatum. We propose that postsynaptic transport of recombinant particles was likely responsible for the distribution of TK in the globus pallidus on both bFGF-treated and untreated sides. In summary, we found that bFGF acts as an adjuvant for distribution of AAV-2 in rat brain.
Hadaczek
Piotr
P
Laboratory of Molecular Therapeutics, Neurological Surgery, University of California, San Francisco, San Francisco, CA 94103, USA. piotr@itsa.ucsf.edu
Mirek
Hanna
H
Bringas
John
J
Cunningham
Janet
J
Bankiewicz
Krys
K
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D000229:Dependovirus / Q000235:genetics*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D007150:Immunohistochemistry; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes
D016222:Fibroblast Growth Factor 2; D013937:Thymidine Kinase