RNAi-mediated inhibition of RHO kinase for treatment of ocular disorders

a technology of rho kinase and rnai, which is applied in the direction of drug compositions, genetic material ingredients, cardiovascular disorders, etc., can solve the problems of high resistance to fluid drainage from the eye, short small molecule-based therapies, vasodilation and conjunctival hyperemia, etc., and achieve the effect of lowering intraocular pressur

Inactive Publication Date: 2007-06-28
ALCON RES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025] The present invention provides an advantage over small molecule inhibitors of Rho kinase since an undesirable side effect of current small molecule therapies, e.g., hyperemia, can be dissociated from the desirable effect of lowering intraocular pressure.

Problems solved by technology

POAG is characterized by the degeneration of the trabecular meshwork, resulting in abnormally high resistance to fluid drainage from the eye.
However, treatment with small molecule inhibitors of Rho kinase also causes vasodilation and conjunctival hyperemia.
In addition, the efficacy of small molecule-based therapies is relatively short-lived requiring repeated dosing during each day and, in some cases, the efficacy decreases with time.

Method used

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  • RNAi-mediated inhibition of RHO kinase for treatment of ocular disorders
  • RNAi-mediated inhibition of RHO kinase for treatment of ocular disorders
  • RNAi-mediated inhibition of RHO kinase for treatment of ocular disorders

Examples

Experimental program
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example 1

Interfering RNA for Specifically Silencing ROCK1 in Trabecular Meshwork Cells

[0106] The present study examines the ability of ROCK1-interfering RNA to knock down the levels of endogenous ROCK1 expression in cultured human glaucomatous trabecular meshwork (TM) cells.

[0107] Transfection of GTM-3 cells (Pang, I. H., et al., 1994 Curr Eye Res. 13:51-63) was accomplished using standard in vitro concentrations (100 nM) of ROCK1 or ROCK2 siRNAs, or a non-targeting control siRNA and DHARMAFECT® #1 transfection reagent (Dharmacon, Chicago, Ill.). All siRNAs were dissolved in 1× siRNA buffer, an aqueous solution of 20 mM KCl, 6 mM HEPES (pH 7.5), 0.2 mM MgCl2. ROCK1 protein expression was evaluated by western blot analysis 72 hours post-transfection. The ROCK1 siRNAs are double-stranded interfering RNAs having specificity for the following targets: siROCK1#1 targets SEQ ID NO:23; siROCK1#2 targets SEQ ID NO:29; siROCK1#3 targets SEQ ID NO:10; siROCK1#4 targets SEQ ID NO:9. The siROCK2 seque...

example 2

Interfering RNA for Specifically Silencing ROCK2 in Trabecular Meshwork Cells

[0109] The present study examines the ability of ROCK2-interfering RNA to knock down the levels of endogenous ROCK2 expression in cultured human glaucomatous trabecular meshwork (TM) cells.

[0110] Transfection of GTM-3 cells (Pang, I. H., et al., 1994 Curr Eye Res. 13:51-63) was accomplished using standard in vitro concentrations (100 nM) of ROCK1 or ROCK2 siRNA, or a non-targeting control siRNA and DHARMAFECT® #1 transfection reagent (Dharnacon, Chicago, Ill.). ROCK2 protein expression was evaluated by western blot analysis 72 hours post-transfection. The ROCK2 siRNAs are double-stranded interfering RNAs having specificity for the following targets: siROCK2#1 targets SEQ ID NO:33; siROCK2#2 targets SEQ ID NO:38; siROCK2#3 targets SEQ ID NO:34; siROCK2#4 targets SEQ ID NO:39. At 100 nM, each of the four ROCK2 siRNAs decreased ROCK2 expression relative to a non-targeting control siRNA and relative to a pool...

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Abstract

RNA interference is provided for inhibition of Rho kinase mRNA expression for treating patients with ocular disorders, particularly for treating intraocular pressure, ocular hypertension and glaucoma. Rho kinase mRNA targets include mRNA for ROCK1 and ROCK2.

Description

[0001] The present application claims the benefit of co-pending U.S. Provisional Patent Application Ser. No. 60 / 754,094 filed Dec. 27, 2005, the text of which is specifically incorporated by reference herein.FIELD OF THE INVENTION [0002] The present invention relates to the field of interfering RNA compositions for inhibition of expression of Rho kinase mRNA targets in ocular disorders, particularly for reducing intraocular pressure in the treatment of ocular hypertension and glaucoma. BACKGROUND OF THE INVENTION [0003] Glaucoma is a heterogeneous group of optic neuropathies that share certain clinical features. The loss of vision in glaucoma is due to the selective death of retinal ganglion cells in the neural retina that is clinically diagnosed by characteristic changes in the visual field, nerve fiber layer defects, and a progressive cupping of the optic nerve head (ONH). One of the main risk factors for the development of glaucoma is the presence of ocular hypertension (OHT), i....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C12N15/113
CPCA61K31/7084C12N15/1137C12N2310/14A61P27/00A61P27/02A61P27/06A61P43/00A61P9/12C12N15/11C12N15/63
Inventor CHATTERTON, JON E.CLARK, ABBOT F.
Owner ALCON RES LTD
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