HSV-1 vector-delivered FGF2 to the retina is neuroprotective but does not preserve functional responses

Fibroblast growth factor 2 (bFGF, FGF2) exhibits mitogenic, angiogenic, wound healing, and neuroprotective properties. Infusion of FGF2 in vivo to treat neurodegenerative disorders in animal models results in increased survival of damaged neurons, but these effects are transient. To test the feasibility of HSV vector-delivered FGF2 for neuroprotection, we inserted the FGF2 gene under the control of the HCMV immediate-early promoter into an attenuated avirulent HSV-1 vector. Transduction with FGF2/HSV-1 virus promoted survival of PC12 cells, induced differentiation of these cells to the neuronal phenotype in vitro, and protected PC12 neuronal cells from death induced by nerve growth factor withdrawal. The attenuated FGF2/HSV-1 virus was able to deliver and direct expression of the FGF2 gene in the eye. Delivery prior to light exposure in a rat model of retinal degeneration resulted in significant protection against photoreceptor loss. However, functional ERG responses were not detected. Treatment of normal eyes with the vector alone suppressed ERGs, which were only partially restored in eyes receiving the FGF2 vector. Thus, although the FGF2-HSV-1 virus induced preservation of cell and tissue structure, this was not sufficient to protect photoreceptor function.