Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa.
We designed experiments to evaluate the therapeutic potential of glial cell line derived neurotrophic factor (GDNF) to rescue photoreceptors from genetically determined cell death. Gene transfer of the neurotrophic factor to the retina was achieved via a recombinant adeno-associated virus (rAAV) vector containing the chicken beta-actin promoter/immediate early cytomegalovirus enhancer (CBA) driving the human GDNF gene. We delivered AAV-CBA-GDNF to the retinas of an animal model of retinitis pigmentosa, the TgN S334ter-4 rhodopsin line of transgenic rats. Immunohistochemical studies localized AAV-CBA-GDNF-derived recombinant protein to cell bodies, inner segments, and outer segments of photoreceptor cells as well as to retinal pigment epithelial cells. We assessed the effect of viral delivery by morphometric and electroretinographic analysis. These experiments showed that GDNF vector treatment leads to increased rod photoreceptor survival as indicated by morphometric analysis of outer nuclear layer thickness. AAV-CBA-GDNF-treated retinas also demonstrated functional improvement by the substantially increased amplitude of electroretinograms. AAV-CBA-GDNF delivery had a significant rescue effect on photoreceptor degeneration in this animal model.
McGee Sanftner
L H
LH
Department of Vision Science, University of California, Berkeley, California 94720, USA.
Abel
H
H
Hauswirth
W W
WW
Flannery
J G
JG
D000199:Actins / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D000229:Dependovirus / Q000235:genetics*; D004596:Electroretinography; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D049452:Green Fluorescent Proteins; D007124:Immunoenzyme Techniques; D008164:Luminescent Proteins / Q000378:metabolism; D023421:Models, Animal; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D010786:Photoreceptor Cells / Q000502:physiology; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000199:Actins; D017931:DNA Primers; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008164:Luminescent Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins