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Karine Bigot, Pauline Gondouin, Pierrick Montagne, Romain Benard, Emilie Picard, Yves G Courtois, Ronald Buggage, Thierry Bordet, Francine F Behar-Cohen; A Non-Viral Gene Therapy Approach for Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5655.
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Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision. Currently, there is no effective treatment for RP, though viral vector-mediated gene replacement therapies offer promise. Whether RP patients may benefit from a neuroprotective approach is not known and needs to be further explored. Herein, we evaluated the neuroprotective effect of a plasmid construct coding for the human transferrin (Tf) (EYS611) in two rat models of retinal degeneration, the Light-Induced Degeneration model (LID) and the N-methyl- N–nitrosourea (MNU) intoxication model.
Photoreceptor degeneration was induced by exposing dark-adapted albinos rats to intense white light (6,500 lux) for 24 hours (LID) or by intraperitoneal injection of 60 mg/kg MNU, leading to about 60-70% outer nuclear layer (ONL) cell loss in a week. Efficacy of EYS611 (30 µg/eye) administered 3 days prior insults was assessed by changes in the electroretinographic (ERG) response and in the histology of the retina.
ET of EYS611 into the ciliary muscle resulted in Tf protein secretion in all the compartments of the eye. In the LID model, EYS611 significantly preserved the ONL both in the posterior and in the inferior poles (54% mean rescue). Importantly, both a- and b-waves scotopic amplitudes were significantly preserved after light exposure in EYS611-treated rats while no residual ERG response could be monitored in untreated animals. Similarly, the outer blood-retinal barrier was drastically disrupted in light-exposed animals but preserved in EYS611-treated animals as determined by about 68% reduction in albumin leakage into the retina. EYS611 gene delivery also reduced by 90% photoreceptor apoptosis induced by MNU intoxication in rat confirming that iron blockade could interfere with photoreceptor death processes.
Iron accumulation is catalyzing both oxidative stress and inflammation in retinal diseases. These results suggest that a non-viral gene therapy targeting iron accumulation may slow down retinal degeneration by inhibiting photoreceptor cell loss. In ongoing experiments we are exploring whether these protective effects in very acute and severe models of retinal degeneration could positively translate in the context of chronic slowly progressive diseases established in rat models of RP.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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