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Elodie Touchard, Peter Heiduschka, Marianne Berdugo, Laura Kowalczuk, Pascal Bigey, Sabine Chahory, Christelle Gandolphe, Jean-Claude Jeanny, Francine Behar-Cohen; Neuroprotection And Neurotoxicity Of The Sustained Intraocular Delivery Of Gdnf In Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6416.
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The ciliary muscle electrotransfer (CM ET) technology, developed and patented by our team, is an electrically-assisted non-viral gene therapy method enabling the local, calibrated and sustained production of any therapeutic protein into the vitreous. Our aim was to determine whether Glial cell line-Derived Neurotrophic Factor (GDNF) secreted by this technology could prolong photoreceptor (PR) survival in a rat model of retinitis pigmentosa (RP).
Experiments were performed in dystrophic Royal College of Surgeon’s (RCS) rats. Endogenous expression of GDNF in the retina and ocular media was analyzed by western-blot and ELISA as a function of age. Injection and ET of increasing amounts (30 vs 60µg) of a rat GDNF-encoding plasmid (pVAX2-GDNF), or the empty backbone (pVAX2), were performed in the CM at post-natal (PN) day 16-20. Anterior segment explants collected 6 days and 7 months after ET were maintained in ex vivo culture for 24 hours to quantify GDNF production in culture supernatants. Morphological and functional rescue of photoreceptors (PR) were assessed around PN50, 70 and 90 by measuring retinal layers thickness on histological sections and by recording scotopic electrophysiological responses and optokinetic responses.
Endogenous GDNF levels dropped during retinal degeneration in untreated eyes, opening a therapeutic window for GDNF supplementation. CM fibers transduced with pVAX2-GDNF actively secreted GDNF for at least 7 months after ET. The continuous release of GDNF following a single ET of 30µg of plasmid delayed PR loss as well as retinal functions until at least PN70 in comparison to pVAX2 treated control eyes. Unexpectedly, increasing the amount of plasmid used from 30 to 60 µg accelerated PR degeneration and the loss of electrophysiological responses.
This study demonstrates that the continuous release of appropriate levels of GDNF could be useful in the management of RP but also warns against potential retinal toxic effects associated with the use of high doses of GDNF. Further studies may be required to determine toxicity threshold for a safe use. Drug delivery systems allowing a controllable and sustained release of therapeutic proteins, like the CM ET technology, could be a safe option to maintain GDNF concentration within a defined therapeutic window.
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