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E. Touchard, L. Kowalczuk, P. Bigey, C. Gandolphe, L. Jonet, J.-C. Jeanny, F. Behar-Cohen; Ciliary Muscle Secretion of Neurotrophic Factors After Plasmid Electrotransfer Delays Photoreceptor Loss in a Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2989.
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© ARVO (1962-2015); The Authors (2016-present)
We have demonstrated that sustained secretion of proteins is achieved in intraocular media after ciliary muscle electrotransfer (CM-ET) of plasmids. Our aim was to determine whether ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) secreted after ET could prolong photoreceptor (PR) survival in RCS rats.
Intraocular fluids levels of rGDNF and rCNTF were measured in dystrophic RCS rats and nondystrophic controls at 75 post-natal day (PN75) using ELISA. The cDNA of GDNF and CNTF, amplified from rat brain RNA, were subcloned in a pVAX2 backbone (CMV promoter) and secretion after CM-ET was evaluated in PN75 RCS rats for GDNF and in 20 weeks old albinos rabbits for CNTF. To evaluate the effect on PR rescue, ET of 30µg of each plasmid was performed in PN18 RCS rats (8 pulses, 200V/cm, 20ms, 5Hz) and ONL thickness was measured on PN75 eye sections. Untreated RCS rats and nondytrophic rats were used as controls.
At PN75, GDNF level was lower in intraocular media of dystrophic RCS rats compared to controls, whereas CNTF level was similar. CM-ET of pVAX2-rGDNF or pVAX2-rCNTF allowed for the secretion of the relative proteins in ocular media. As shown by ONL thickness measurements, a significant rescue of PR was demonstrated in the dystrophic RCS rats with a greater effect with rGDNF (9.7µm±0.1) compared to rCNTF (6.8±0.8) and controls (4.3±0.2).
Ciliary muscle ET is a simple, safe and efficient method to deliver neurotrophic factors for the treatment of degenerative retinal disease. It allows a sustained secretion of GDNF in the vitreous resulting in significant rescue of photoreceptors.This work was supported by the European project EVI-GENORET (LSHG-CT-2005-512036) and the ANR EMERGENCE project (ANR05EMPB001-02).
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