Transduction of axotomized retinal ganglion cells by adenoviral vector administration at the optic nerve stump: an in vivo model system for the inhibition of neuronal apoptotic cell death
S. Kugler et al., Transduction of axotomized retinal ganglion cells by adenoviral vector administration at the optic nerve stump: an in vivo model system for the inhibition of neuronal apoptotic cell death, GENE THER, 6(10), 1999, pp. 1759-1767
Axotomy of the rat optic nerve leads to apoptotic cell death of retinal gan
glion cells (RGCs). We have used adenoviral vectors to transduce RGCs from
the cut optic nerve stump, a paradigm in which only those neurons are trans
duced which are directly affected by the axonal lesion. Transgenes encoded
by the vectors were p35 and CrmA, which are potent intracellular anti-apopt
otic proteins. We found :that p35. but not CrmA exerted significant rescue
effects :;lon RGCs 14 days after axotomy. Expression of the transgenes was
driven by the murine CMV (MCMV) promoter The respective mRNAs were detectab
le 7 days but not 14 days after transduction. Since surviving RGCs were pre
sent beyond the time-point of detectable transcription of the p35 transgene
, we conclude that apoptosis has been efficiently inhibited. In addition, w
e observed that transduction with two control vectors without a transgene i
n El also resulted in a minor but significant RGC rescue, implicating neuro
protective effects due to adenoviral transduction itself. This system will
be useful in dissecting the pathways leading to neuronal cell death after a
xonal lesions and in the evaluation of the important question whether the c
ellular suicide program can be reverted to survival by therapeutic gene del
ivery.