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Inhibition of choroidal neovascularization

a choroidal neovascularization and choroidal neovascularization technology, applied in the direction of cardiovascular disorders, drug compositions, amide active ingredients, etc., can solve the problems of unstable hdl, conflicting data regarding the association between serum hdl and amd, and plateauing efficacy, so as to reduce the inability to efflux cholesterol from the intracellular space

Inactive Publication Date: 2012-11-29
WASHINGTON UNIV IN SAINT LOUIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods for treating a disease called age-related macular degeneration (AMD) by increasing the expression of a protein called ABCA1. This protein helps to regulate the formation of new blood vessels in the eye, which can cause blindness. The methods involve using either an activator of ABCA1 or an inhibitor of cholesteryl ester transfer protein (CETP) activity. The activator can be a compound called an agonist for PPARα, PPARβ, or PPARδ, while the inhibitor can be a compound called torcetrapib, anacetrapib, or dalcetrapib. By increasing the expression of ABCA1, the methods hope to improve the regulation of angiogenesis and prevent blindness in patients with AMD.

Problems solved by technology

AMD is the leading cause of blindness and market size is currently about 4-6 billion USD.
Only anti-VEGF approaches are currently available and efficacy has plateaued.
However, data regarding the association between serum HDL levels and AMD are conflicting (The Eye Disease Case-Control Study Group, Arch.
The end result of this exchange can be the generation of unstable HDL.
However, these studies involve systemic administration of CETP inhibitors.
It is thus apparent that the biologic pathways that connect macrophage-mediated inflammation, cholesterol regulation and age in AMD are highly complex and cannot be explained by a simple association of increased risk and abnormal serum lipid component levels.
However, these workers found that previously reported results from HDL loci was inconsistent with a straightforward correlation between HDL levels and AMD.
There are currently no approaches that target cholesterol efflux as a mechanism to prevent blindness from wet AMD.

Method used

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  • Inhibition of choroidal neovascularization
  • Inhibition of choroidal neovascularization
  • Inhibition of choroidal neovascularization

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0082]This example illustrates effects of age on cholesterol efflux.

[0083]To determine whether age altered cholesterol efflux in macrophages, we analyzed the expression patterns of ABCA1 and ABCG1 in these cells. Quantitative analysis of gene expression by real time PCR demonstrated an age-associated reduction in levels of ABCA1 and ABCG1 expression in splenic, peritoneal and eye macrophages and PBMCs (FIG. 1a-d). Analysis of ABCA1 and ABCG1 protein levels in peritoneal macrophages isolated from either young (18 months) mice by western blotting as well as flow cytometry confirmed that reduced gene expression of ABCA1 and ABCG1 with age translated to reduced protein expression (FIG. 1e-f).

[0084]Because of the critical role of ABC transporters in lipid metabolism in macrophages, we examined whether the age-associated decrease of ABCA1 and ABCG1 altered the intracellular lipid load within macrophages and influenced formation of foam cells. Thioglycollate elicited young or old peritonea...

example 2

[0088]This example illustrates that Abca1 depletion affects macrophage regulation of vascular endothelial cell proliferation and pathological angiogenesis.

[0089]To determine the contribution of individual ABC transporters in age-associated dysfunction of macrophage cholesterol homeostasis, we investigated the effects of selective Abca1 or Abcg1 deletion on effector function. Recent studies have demonstrated that macrophage polarization can play a pivotal role in determining their ultimate effector functions including their ability to regulate angiogenesis (Macrophages Inhibit Neovascularization in a Murine Model of Age-Related Macular Degeneration. PLoS Med 3(8): e310. doi:10.1371 / journal.pmed.0030310 2006; Kelly, J., et al., Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J. Clin. Invest. 117, 3421-3426, 2007; Mosser, D. M. The many faces of macrophage activation. J. Leukoc. Biol. 73, 209-212, 2003; Mantovani, A., et al., Macrophage...

example 3

[0092]This example illustrates that a cholesterol-rich diet accelerates a senescent macrophage phenotype.

[0093]As shown in FIG. 2, ABCA1 / G1 transporters within macrophages regulate intracellular cholesterol efflux. We next investigated the effect of chronic dietary lipid / cholesterol burden on macrophage function using diet-induced obesity (DIO) mice as a model of high fat / cholesterol fed mice. Quantitative analysis of intracellular cholesterol content demonstrated that DIO macrophages had significantly higher levels of total cholesterol compared to age-matched controls at both 3 and 6 months of age (FIG. 3e). To determine whether high fat / cholesterol stress altered the ability of DIO macrophages to regulate vascular proliferation, we incubated young DIO macrophages with HMVECs and assessed their proliferation. DIO macrophages were unable to inhibit HMVECs proliferation (FIG. 3f). In addition, DIO macrophages demonstrated an impaired ability to regulate CNV in vivo (FIG. 3g-h) indica...

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Abstract

Methods of treatment of diseases that include or are characterized by inappropriate or pathological neovascularization are disclosed. These diseases include diseases of the eye, such as diabetic retinopathy, retinopathy of prematurity, and choroidal neovascularization which can occur in age-related macular degeneration (AMD). Disclosed methods include administering agents that cause directly or indirectly upregulation of the ABCA1 transporter protein in macrophages. These agents include, without limitation, LXR agonists. In some embodiments, inhibitors of CETP expression or activity can also be effective. Administration routes can include, without limitation, intraocular, periocular, or systemic administration.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application No. 61 / 489,656, filed May 24, 2011. This application is incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT[0002]This invention was made with the support of government grant 1R01EY019287-01A1 from the National Institutes of Health. The government of the United States of America has certain rights in this invention.REFERENCE TO A SEQUENCE LISTING[0003]The Sequence Listing, which is a part of the present disclosure, includes a text file comprising primer nucleotide and / or amino acid sequences of the present invention. The subject matter of the Sequence Listing is incorporated herein by reference in its entirety. The information recorded in computer readable form is identical to the written sequence listing.INTRODUCTION[0004]There are a number of diseases that include or are characterized by inappropriate or pathological neovascularization...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61K31/575A61K31/58A61K31/195A61P27/02A61K31/421A61K31/216A61K35/12A61K31/7105A61K31/18A61K31/4706
CPCC12N15/113A61K31/18A61K31/195A61K31/421A61K38/1709A61K31/575A61K31/58A61K9/0048A61K31/4706A61K31/47A61K31/265A61P27/02A61K39/46432A61K39/4622C12N5/0645A61K39/4614A61K9/0053A61K9/0019C12N2501/999C12N2502/11
Inventor APTE, RAJENDRA S.
Owner WASHINGTON UNIV IN SAINT LOUIS
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