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A. Jimenez, A. Sesto, J. Pintor, A. Mediero, A. Peral; Na+/K+ ATPase: A New Target for Treating Ocular Hypertension by RNAi. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4809.
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© ARVO (1962-2015); The Authors (2016-present)
To find a new treatment for ocular hypertension and glaucoma, studying the effect on intraocular pressure (IOP) of ATPases Na+/K+ siRNA topical administration in New Zealand White rabbits
We have designed several siRNAs for the following ATPase genes: Na+/K+ ATPase alpha 1, alpha 2, beta 1 and beta 2. After an in vitro validation, we tested in vivo the effect on IOP levels using the different siRNA sequences. siRNAs were administered in saline solution (0.9% w/v) to a final volume of 40ul in one eye during four consecutive days and the opposite eye was taken as a control applying 40ul of sterile saline (0.9% w/v). Two rabbits were used in each experiment. IOP levels were measured from the beginning of the experiment several times a day along ten days. Also, we performed control in vivo studies, following the protocol above described, using both commercial drugs and previously validated siRNAs, targeting carbonic anhydrases and beta adrenergic receptors, to evaluate the ATPase siRNA effect on IOP levels.
On one hand, the ATP1A1 and ATP1A2 siRNA reduced IOP in 18.13±1.39 % during 96 hours and in 15.28 ± 1.92 for 75 hours respectively. On the other hand, the ATP1B2 siRNA caused a decrease in IOP of 16.32 ± 0.91 % lasting 88 hours; while the ATP1B1 siRNA (n=2) didn’t produce any effect. The commercial drug Xalatan, used as a control, reduced IOP 23.40 ± 2.36 % during 5 to 6 hours. The IOP decreases obtained by the instillation of siRNAs targeting Na+/K+ ATPases alpha1, alpha2 and beta2 were similar to those reached with carbonic anhydrases and beta adrenergic receptors validated siRNAs.
These results confirm the Na+/K+ ATPases as new therapeutic targets to treat ocular hypertension. The decrease of IOP by siRNAs targeting Na+/K+ ATPases is similar to that produced by commercial drugs and also by other siRNAs targeting carbonic anhydrases and beta adrenergic receptors. Moreover, siRNA treatment shows a generalized long lasting effect when compared to commercial drugs.
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