RNAi-RELATED INHIBITION OF TNFalpha SIGNALING PATHWAY FOR TREATMENT OF OCULAR ANGIOGENESIS

a technology of tnfalpha signaling pathway and rnai, which is applied in the direction of drug compositions, genetic material ingredients, organic chemistry, etc., can solve the problems of tissue edema, impaired differentiation process, wet or exudative amd, and subsequent loss of cones and rods

Inactive Publication Date: 2009-02-05
ARROWHEAD RES CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The new capillaries commonly have increased vascular permeability or leakiness due to immature barrier function, which can lead to tissue edema.
Differentiation into a mature capillary is indicated by the presence of a continuous basement membrane and normal endothelial junctions between other endothelial cells and pericytes; however, this differentiation process is often impaired during pathologic conditions.
Leakage of the vascular layer leads to wet or exudative AMD and subsequent loss of cones and rods that are vital to vision.
In spite of the prevalence of PSNV, treatment strategies are few and palliative at best.
Thus, interfering with the TNFα pathway may selectively block pathological neovascularization without affecting the normal process.

Method used

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  • RNAi-RELATED INHIBITION OF TNFalpha SIGNALING PATHWAY FOR TREATMENT OF OCULAR ANGIOGENESIS
  • RNAi-RELATED INHIBITION OF TNFalpha SIGNALING PATHWAY FOR TREATMENT OF OCULAR ANGIOGENESIS
  • RNAi-RELATED INHIBITION OF TNFalpha SIGNALING PATHWAY FOR TREATMENT OF OCULAR ANGIOGENESIS

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example 1

Interfering RNA for Specifically Silencing TNFR1 in GTM-3 Cells

[0116]The present study examines the ability of TNFR1 interfering RNA to knock down the levels of endogenous TNFR1 protein expression in cultured GTM-3 cells.

[0117]Transfection of GTM-3 cells (Pang, I. H. et al., 1994. Curr. Eye Res. 13:51-63) was accomplished using standard in vitro concentrations (0.1-10 nM) of TNFR1 siRNAs, siCONTROL RISC-free siRNA, or siCONTROL Non-targeting siRNA #2 (NTC2) and DHARMAFECT® #1 transfection reagent (Dharmacon, Lafayette, Colo.). 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. Control samples included a buffer control in which the volume of siRNA was replaced with an equal volume of 1× siRNA buffer (-siRNA). Western blots using an anti-TNFR1 antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.) were performed to assess TNFR1 protein expression. The TNFR1 siRNAs are double-stranded interfering RNAs having specificity f...

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Abstract

RNA interference is provided for inhibition of tumor necrosis factor α (TNFα) by silencing TNFα cell surface receptor TNF receptor-1 (TNFR1) mRNA expression, or by silencing TNFα converting enzyme (TACE / ADAM17) mRNA expression. Silencing such TNFα targets, in particular, is useful for treating patients having a TNFα-related condition or at risk of developing a TNFα-related condition, such as ocular angiogenesis, retinal ischemia, and diabetic retinopathy.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims priority under 35 U.S.C. §119 to U.S. Provisional Patent Application No. 60 / 953,825 filed Aug. 3, 2007, the entire contents of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to the field of interfering RNA compositions for silencing tumor necrosis factor α (TNFα) by silencing the TNFα cell surface receptor TNF receptor-1 (TNFR1) mRNA, or the TNFα converting enzyme (TACE / ADAM17) mRNA. Silencing such TNFα targets is useful for treatment of patients having a TNFα-related condition or at risk of developing such a condition.BACKGROUND OF THE INVENTION[0003]Pathologic ocular neovascularization (NV) and related conditions occur as a cascade of events that progresses from an initiating stimulus to the formation of abnormal new capillaries. The stimulus appears to be the elaboration of various proangiogenic growth factors such as vascular endothelial growth factor (VEGF),...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7105C07H21/02A61P27/00C12N15/113
CPCC12N15/1137C12N15/1138C12N2310/111C12N2310/319C12N2310/53C12N15/1136C12N2310/141C12N2310/14A61P27/00A61P27/02A61P35/00C12N15/113C12N2310/31C12N2310/32C12N2310/321C12N2310/531
Inventor CHATTERTON, JON E.CLARK, ABBOT F.BINGAMAN, DAVID P.WAX, MARTIN B.TIMMERS, ADRIAN M.
Owner ARROWHEAD RES CORP
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