Potential synergistic protection of retinal ganglion cells from axotomy-induced apoptosis by adenoviral administration of glial cell line-derived neurotrophic factor and X-chromosome-linked inhibitor of apoptosis.
Following transection of the optic nerve (ON) in the adult rat, retinal ganglion cells (RGCs) undergo degeneration, and within 14 days 85% of axotomized RGCs die by apoptosis. Adenoviral delivery of the mammalian caspase inhibitor X-chromosome-linked inhibitor of apoptosis (Ad.XIAP) to the ON stump leads to expression exclusively in RGCs and rescues 18.9% of the RGCs that would degenerate without treatment. Following adenoviral vector injection into the vitreous body, bioactive glial cell line-derived neurotrophic factor (Ad.GDNF) is expressed in the retina and secreted to rescue 22.8% of lesioned RGCs. Here we report that coadministration of Ad.XIAP retrogradely directed to RGCs and intravitreal Ad.GDNF acts synergistically to protect axotomized RGCs. Combination treatment rescued 47.3% of RGCs that would undergo apoptosis without any treatment as opposed to 37.4% that would be expected if the two treatments acted independently. While without treatment only 15% of axotomized RGCs would survive, combination treatment resulted in survival of 55.4% of the total RGC population. These findings underline the neuroprotective potential of synergistic effects of a combination of different treatment strategies.
Straten
Guido
G
Neuroregeneration Laboratory, Department of Neurology, University of Tübingen, D-72076 Tübingen, Germany.
Schmeer
Christian
C
Kretz
Alexandra
A
Gerhardt
Ellen
E
Kügler
Sebastian
S
Schulz
Jörg B
JB
Gravel
Claude
C
Bähr
Mathias
M
Isenmann
Stefan
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D019771:Axotomy; D002470:Cell Survival; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D009414:Nerve Growth Factors / Q000235:genetics*; D018696:Neuroprotective Agents; D011506:Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein