PROLONGED DELIVERY OF BRAIN-DERIVED NEUROTROPHIC FACTOR BY ADENOVIRUS-INFECTED MULLER CELLS TEMPORARILY RESCUES INJURED RETINAL GANGLION-CELLS

In this study, we demonstrate that: (i) injection of an adenovirus (Ad ) vector containing the brain-derived neurotrophic factor (BDNF) gene (Ad.BDNF) into the vitreous chamber of adult rats results in selective transgene expression by Muller cells; (ii) in vitro, higher cells inf ected with Ad.BDNF secrete BDNF that enhances neuronal survival; (iii) in viva, Ad-mediated expression of functional BDNF by Muller cells, t emporarily extends the survival of axotomized retinal ganglion cells ( RGCs); 16 days after axotomyl injured retinas treated with Ad.BDNF sho wed a 4.5-fold increase in surviving RGCs compared with control retina s; (iv) the transient expression of the BDNF transgene, which lasted a pproximate to 10 days, call be prolonged with immunosuppression for at least 30 days, and such Ad-mediated BDNF remains biologically active, (v) persistent expression of BDNF by infected Muller cells does not f urther enhance the survival of injured RGCs, indicating that the effec t of this neurotrophin on RGC survival is limited by changes induced b y the lesion within 10-16 days after optic nerve transection rather th an the availability of BDNF. Thus, Ad-transduced Muller cells are a no vel pathway for sustained delivery of BDNF to acutely-injured RGCs, Be cause these cells span the entire thickness of the retina, Ad-mediated gene delivery to Muller cells may also be useful to influence photore ceptors and other retinal neurons.