RNAi-mediated inhibition of HIF1A for treatment of ocular angiogenesis

Abstract

RNA interference, is provided for inhibition of HIF1A mRNA expression for treating patients with ocular angiogenesis, particularly for treating retinal edema, diabetic retinopathy, sequela associated with retinal ischemia, posterior segment neovascularization (PSNV), and neovascular glaucoma, and for treating patients at risk of developing such conditions.

Description

[0001] The present application claims the benefit of co-pending U.S. Provisional Patent Application Ser. No. 60 / 754,956 filed Dec. 29, 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 hypoxia-inducible factor-1α (HIF-1α), the protein encoded by HIF1A MRNA, in ocular angiogenesis, including those cellular changes resulting from the transcription factor activity of HIF-1α that lead directly or indirectly to ocular neovasularization, retinal edema, diabetic retinopathy, sequela associated with retinal ischemia, posterior segment neovascularization, and neovascular glaucoma, for example. BACKGROUND OF THE INVENTION [0003] Diabetic retinopathy (DR) is an eye disease that develops in diabetes due to changes in the cells that line blood vessels, i.e. the retinal microvascular endothelium. During diabetes mellitus, hyperglycemia can...

AI Technical Summary

Benefits of technology

[0010] The present invention is directed to interfering RNAs that silence HIF1A mRNA expression, thus decreasing transcriptional activity of HIF-1 inducible genes and treating ocular angiogenesis by effecting a lowering of ocular pre-angiogenic and angiogenic cellular activity.

Problems solved by technology

During diabetes mellitus, hyperglycemia can cause damage in a number of ways.

For example, glucose, or a metabolite of glucose, binds to the amino groups of proteins, leading to tissue damage.

In addition, excess glucose enters the polyol pathway resulting in accumulations of sorbitol.

Sorbitol cannot be metabolized by the cells of the retina and can contribute to high intracellular osmotic pressure, intracellular edema, impaired diffusion, tissue hypoxia, capillary cell damage, and capillary weakening.

Weakened capillaries lead to aneurysm formation and further leakage.

These effects of hyperglycemia can also impair neuronal functions in the retina.

As the diabetes-induced microvascular pathology progress, retinal capillaries eventually become occluded and lead to multifocal areas of ischemia hypoxia within the retina.

These pathologic new blood vessels grow into the vitreous and can cause loss of sight, a condition called proliferative diabetic retinopathy (PDR), since the new blood vessels are fragile and tend to leak blood into the eye.

Both therapies involve occlusion of affected vasculature, which results in permanent, laser-induced damage to the retina, and does not address the underlying cause of neovascularization.

Disruption of the interaction between the HIF-1 transcription factor and the hypoxia response element in oxygen sensitive promoters using conventional small molecule inhibitors is likely to be very difficult.

Furthermore, the silencing of individual downstream effectors of HIF-1, such as VEGF or RTP801, may only partially block neovascularization.

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