Prevention and treatment of retinal ischemia and edema

a retinal ischemia and edema technology, applied in the field of retinal ischemia and edema prevention and treatment, can solve the problems of retinal ischemia and/or retinal edema reduction, and achieve the effects of inhibiting leukocyte interaction, inhibiting leukocyte interaction, and inhibiting leukocyte interaction

Inactive Publication Date: 2008-01-24
CHILDRENS MEDICAL CENT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010] The present invention also relates to methods of treating diabetic retinopathy by administering an ICAM-1, CD18, CD11b and/or VEGF antagonist and at least one additional antagonist that inhibits the binding of a leukocyte to an endothelial cell or to another leukocyte. The additional antagonist can be an integrin antagonist (e.g., an integrin subunit antagonist such as CD18 and/or CD11b), a selectin antagonist, a leukocyte adhesion-inducing or growth factor antagonist, or adhesion molecule antagonist. The additional antagonist can be, for example, another ICAM antagonist (e.g., an antagonist that is specific for a different portion or epitope of the ICAM-1 molecule), a PCAM antagonist or a VCAM antagonist. The types of integrin antagonists, selectin antagonists, and leukocyte adhesion-inducing or growth factor antagonists are described herein.
[0011] The invention also encompasses a method of inhibiting leukocyte interaction, comprising contacting a leukocyte, an endothelial cell or a leukocyte adhesion-inducing cytokine, with a compound or antagonist, as defined herein. The compound can be an integrin antagonist (e.g., an integrin sub-unit antagonist such as CD18 and/or CD11b), a selectin antagonist, an adhesion molecule antagonist or a leukocyte adhesion-inducing cytokine or growth factor antagonist. In particular, the invention relates to a method of inhibiting leukocyte interaction, comprising contacting an endothelial cell with an adhesion molecule antagonist (e.g., ICAM-1 specific antagonist), an integrin subunit antagonist (e.g., CD18 and/or CD11b specific antagonist), or a leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist (e.g., TNF-1α, IL-1β, MCP-1 and VEGF antagonist).
[0012] The invention also pertains to a method of preven

Problems solved by technology

Administration of this antagonist results in a d

Method used

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  • Prevention and treatment of retinal ischemia and edema
  • Prevention and treatment of retinal ischemia and edema
  • Prevention and treatment of retinal ischemia and edema

Examples

Experimental program
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Effect test

example 1

Prevention of Leukostasis and Vascular Leakage Diabetic Retinopathy via ICAM-1 Inhibition

[0091] Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and non-perfusion. This study demonstrates that diabetic retinal vascular leakage and non-perfusion are temporally and spatially associated with retinal leukocyte stasis (leukostasis) in the rat model of streptozotocin-induced diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1). ICAM-1 blockade with a monoclonal antibody prevents diabetic retinal leukostasis (e.g., resulting in ischemia) and vascular leakage (e.g., resulting in edema) by 48.5% and 85.6%, respectively. These data identify the causal role of leukocytes in the pathogenesis of diabetic retinopathy and demonstrate the important utility o...

example 2

Integrin-Mediated Neutrophil Adhesion and Retinal Leukostasis in Diabetes

Introduction:

[0107] Leukocyte-endothelial cell interactions in tissues are mediated by adhesion molecules expressed on the surface of leukocytes and endothelial cells. Immunoglobulin superfamily molecules such as ICAM-1 are expressed on endothelial cells and bind to β2-integrins expressed on leukocytes. The integrins are transmembrane receptors that consist of noncovalently bound heterodimers composed of α- and β-chains. The 2-integrins are operative in leukocyte adhesion and include LFA-1 (lymphocyte function associated antigen, CD11a / CD18), Mac-1 (leukocyte adhesion receptor, CD11b / CD18) and p150 / 95 (CD11c / CD18). Each of the β2-integrins has a common α-chain in combination with a unique α-chain. CD18 is required for the firm attachment of healthy human neutrophils to human umbilical vein endothelial cells.

[0108] In vivo studies from our laboratory have investigated the role of leukocytes in diabetic retin...

example 3

Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Vascular Permeability is Mediated by ICAM-1

SUMMARY

[0130] Two prominent VEGF-induced retinal effects are vascular permeability and capillary non-perfusion. The mechanisms by which these effects occur are not completely known. Using a rat model, it is shown that intravitreous injections of VEGF precipitate an extensive retinal leukocyte stasis (leukostasis) that coincides with enhanced vascular permeability and capillary non-perfusion. The leukostasis is accompanied by the upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in the retina. The inhibition of ICAM-1 bioactivity with a neutralizing antibody prevents the permeability and leukostasis increases by 79% and 54%, respectively. These data are the first to demonstrate that a non-endothelial cell type contributes to VEGF-induced vascular permeability. Additionally, they identify a potential mechanism for VEGF-induced retinal capillary non-perfusion.

[013...

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Abstract

The present invention relates to methods of treating retinopathy, retinal ischemia and/or retinal edema comprising administering an integrin or integrin subunit antagonist, leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist, a selectin antagonist or adhesion molecule antagonist.

Description

RELATED APPLICATION [0001] This application is a Continuation of U.S. application Ser. No. 10 / 364,922, filed Feb. 11, 2003, which is a Continuation of U.S. application Ser. No. 09 / 474,523 filed Dec. 29, 1999, which is a Continuation-in-Part of U.S. application Ser. No. 09 / 248,752, filed Feb. 12, 1999, which claims the benefit of U.S. Provisional Application No. 60 / 114,221, filed Dec. 30, 1998. The entire teachings of the above applications are incorporated herein by reference.GOVERNMENT SUPPORT [0002] The invention was supported, in whole or in part, by a grant 2P01 HL32262-15 from the National Institutes of Health. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] Diabetes affects over 16 million Americans. The World Health Organization indicates that diabetes afflicts 120 million people worldwide, and estimates that this number will increase to 300 million by the year 2025. Diabetics are faced with numerous complications including kidney failure...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K31/7088A61K45/00A61P27/00A61P27/02C07K16/28
CPCA61K9/0048A61K31/7088A61K33/08C07K16/2845A61K45/06A61K2039/505C07K16/2821A61K33/10A61P27/00A61P27/02
Inventor ADAMIS, ANTHONY P.
Owner CHILDRENS MEDICAL CENT CORP
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