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A. Jimenez, A. Mediero, P. Loma, J. Pintor, A. Peral, V. Gónzalez; Efficacy of Topically Administered siRNAs in Glaucoma Treatment: In vivo Results in Hypertensive Model. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4054.
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© ARVO (1962-2015); The Authors (2016-present)
To demonstrate in vivo efficacy of topically administered siRNAs for the treatment of ocular hypertension associated to open angle glaucoma. Results are presented in a New Zealand white rabbit model of ocular hypertension induced by water loading.
Different siRNAs against proteins involved in intraocular pressure (IOP) regulation, previously validated by in vitro assays, were tested in vivo in New Zealand white rabbits to evaluate their effect in preventing the increase of IOP levels after water loading. siRNAs were administered as eyedrops in phosphate buffered saline solution (0.9% w/v). Different experiments were performed in order to obtain data concerning maximal IOP in animals treated with therapeutic siRNAs compared to scramble and vehicle treated animal groups, dose-response studies, and analysis of in vivo downregulation.
This hypertensive rabbit model has been previously described by several authors by the administration 60 mL/Kg by oral gavage. The main advantage of this model over other experimental models of ocular hypertension is that administration of irritant compounds or techniques that are traumatic to the eye are avoided, leaving the ocular structures intact. In this model a commercial drug, Alphagan, induces an IOP reduction in a dose-response manner. We tested in a rabbit hypertensive model two different siRNAs targeting carbonic anhydrase IV (CA4) and β2- adrenergic receptor (ADRB2). Previous results in a normotensive rabbit showed a decrease in IOP of 14.47±5% and 21.81±1.5% for CA4 and ADRB2, respectively. In this hypertensive model SYL04004 and SYL040012 clearly prevent hypertension induced by oral gavage. The EC50 value was calculated using dose-response studies, and the administration pattern studies suggested that consecutive doses are the most effective treatment.
These results suggest that siRNA is a new therapeutic approach to treat ocular hypertension and open angle glaucoma. The IOP decrease obtained with siRNAs is higher and more sustained than those produced by commercial drugs in both model normotensive and hypertensive rabbits.
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