Glial cell line-derived neurotrophic factor (
GDNF) is one of the candidate molecules among
neurotrophic factors proposed for a potential treatment of
retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged
neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous
GDNF levels dropped during
retinal degeneration time course, opening a therapeutic window for
GDNF supplementation. We showed that after a single electrotransfer of 30 μg of
GDNF-encoding plasmid in the rat ciliary muscle,
GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of
GDNF delayed photoreceptors (PRs) as well as
retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the
GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of
GDNF delivery through non-viral gene
therapy in RP; (ii) establishing the efficacy of intravitreal administration of
GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of
GDNF within the eye/retina.