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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 promising non-viral gene therapy approach for retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3387. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision. As there is no effective treatment for RP neuroprotective, approaches to slow the disease progression merit further exploration. We previously demonstrated that intraciliary muscle electrotransfection (ET) of a plasmid encoding the human transferrin (hTf) (EYS611) slowed down disease progression in two rat models of induced-retinal degeneration supporting the therapeutic potential of iron chelation in RP. Herein, we benckmarked the effect of EYS611 against two antioxidants in the rat light-induced degeneration model (LID) and evaluated the neuroprotective effect of EYS611 in the RCS rat model of inherited retinal dystrophy.
Photoreceptor degeneration was induced by exposing dark-adapted albino rats to intense white light (6,500 lux) for 24 hours (LID). EYS611 (0.3 to 30 µg/eye) was electrotransfered 3 days prior insult (D0) while N-acetylcysteine amide (NACA, 250 mg/kg) and carnosic acid (CA, 25 mg/kg) were intraperitonaly injected on D-1 and D1 and from D-5 to D0, respectively. 28-day-old RCS rats were treated with a single ET of EYS611 (15 µg/eye). Efficacy was assessed by changes in the electroretinographic (ERG) response and retinal histology.
In the LID model, EYS611 significantly preserved the ONL both in the superior and in the inferior poles (70% mean rescue) with dose-effect observed in the superior retina. Importantly, both dark- and light-adapted ERG responses were significantly preserved in EYS611-treated rats at each dose evaluated. The outer blood-retinal barrier (BRB) was drastically disrupted in light-exposed animals but preserved in EYS611-treated animals as determined by about 60% reduction in albumin leakage into the retina. In our experiment, treatment with NACA or CA leaded to poor or no preservation of ONL thickness, ERG function or outer BRB integrity. In RCS rats, EYS611 aministered after disease onset delayed photoreceptor cell loss with 22% mean rescue of ONL thickness on PN45.
These results demonstrate that a non-viral gene therapy administered by ET targeting iron accumulation provides significant protection over antioxidants. Our findings demonstrating preservation of the retina following the administration of EYS611 in retinal degenerative disease models further validates iron overload as a therapeutic target for treatment of RP.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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