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Compositions and methods for treatment of diabetic retinopathy

a technology for diabetic retinopathy and compositions, applied in the field of compositions and methods for treating diabetic retinopathy, can solve the problems of loss of workplace and personal functions following such loss of visual function, and achieve the effect of reducing and/or preventing macular edema

Inactive Publication Date: 2009-06-18
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]In a second aspect a method is provided of treating a subject suffering from macular edema comprising administering to said subject in need thereof a therapeuticall

Problems solved by technology

The loss of workplace and personal function subsequent to such loss of visual function can have devastating impact upon the individual and on the community surrounding that individual as a whole.

Method used

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  • Compositions and methods for treatment of diabetic retinopathy
  • Compositions and methods for treatment of diabetic retinopathy
  • Compositions and methods for treatment of diabetic retinopathy

Examples

Experimental program
Comparison scheme
Effect test

example 1

Affinity Measurements

[0353]The affinities of the small molecules for LFA-1 were measured using fluorescence polarization (FP) in a competitive format with a small molecule antagonist, compound 1 (FIG. 2), as previously described. All measurements were performed in buffer containing 50 mM Hepes, pH 7.2, 150 mM NaCl, 0.05% n-octyglucoside and 0.05% bovine gamma globulins (BGG) and either 1 mM MnCl2, or 1 mM CaCl2 and 1 mM MgCl2. The affinity of compound 1 for LFA-1 was first measured by addition of 2 nM compound 1 to serial dilutions of LFA-1 starting from 1 μM in buffer containing either MnCl2 or CaCl2 and MgCl2. Competition experiments were performed by addition of serial dilutions of antagonists to 2 nM compound 1 (using either 3 nM LFA-1 (in MnCl2) or 40 nM LFA-1 (in CaCl2 and MgCl2)). In the ICAM-1-Ig competition experiments, the LFA-1 concentrations were reduced to 2 and 20 nM LFA-1 in the two divalent cation buffer conditions to maximize inhibition by ICAM-1-Ig. The different L...

example 2

LFA-1 / ICAM-1 and LFA-1 / Small Molecule Enzyme-Linked Immunosorbent Assays (ELISAs)

[0354](A) Antagonist Competition: Small molecules and sICAM-1 were assayed for the ability to disrupt binding of ICAM-1-Ig or a fluorescein-labeled small molecule antagonist, compound 2B, to LFA-1 in a competitive format. Compound 2B is similar to compound 1, but with a longer linker between the small molecule and fluorescein to maximize the binding of the anti-fluorescein detection antibody. 96-well plates were coated with 5 μg / ml (33.3 nM) mouse anti-human β2 integrin (a non-function blocking antibody) in phosphate-buffered saline (PBS) overnight at 4° C. The plates were blocked with assay buffer (20 mM Hepes, pH 7.2, 140 mM NaCl, 1 mM MnCl2, 0.5% bovine serum albumin (BSA) and 0.05% Tween-20) for 1 hour at room temperature. After washing in buffer (50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM MnCl2, and 0.05% Tween-20), 8 nM LFA-1 (LFA-1 / ICAM-1 ELISA) or 2 nM LFA-1 (LFA-1 / small molecule ELISA) were adde...

example 3

Crosslinking of a Radiolabeled, Photoactivatable Analogue of Compound 3 to LFA-1

[0356]Full length human membrane-associated LFA-1 or BSA (0.35 mg / mL [1.4 and 5.3 μM, respectively] in 20 mM Hepes, 150 mM NaCl, 5 mM CaCl2, 5 mM MgCl2, 1 mM MnCl2, and 1% n-octylglucoside, pH 7.2) was incubated overnight at 37° C. with 4.1 μM compound 5, a tritium-labeled photoactivatable analogue of compound 3, in either the presence or absence of 290 μM compound 3. The molar ratio of compound 5 to LFA-1 was 3:1. A 96-well plate precoated with 1% BSA was used for the incubation. Just prior to crosslinking, excess compound 5 was rapidly removed by gel filtration with a G-25 microspin column in a 96-well format equilibrated with the same buffer. The LFA-1 / compound 5 complex was crosslinked by exposure to a high-pressure mercury-vapor lamp (450 watts, Ace glass, Vineland, N.J.). During irradiation, samples were cooled on ice and protected by a 5-mm thick plate of borosilicate glass to minimize protein deg...

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Abstract

The present invention provides compounds and methods for the treatment of diabetic retinopathy. In particular, LFA-1 antagonists are described herein to be used in the treatment of diabetic retinopathy. One aspect of the invention provides for diagnosis of diabetic retinopathy and administration of a LFA-1 antagonist, after the patient is diagnosed with diabetic retinopathy.

Description

CROSS-REFERENCE[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 999,571, filed Oct. 19, 2007, the entire disclosure of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Worldwide, one of the most significant causes of blindness is diabetic retinopathy (DR) which often includes an associated disorder, diabetic macular edema (DME), which is one of the complications of diabetes resulting in microvasculature insult, injury and degeneration in the body, and in particular, the eye. The loss of workplace and personal function subsequent to such loss of visual function can have devastating impact upon the individual and on the community surrounding that individual as a whole. Nearly all individuals with diabetes demonstrate some degree of diabetic retinopathy, and the numbers of diabetic patients are increasing, therefore there is need for more effective treatments for vision loss and the symptoms of DR and associ...

Claims

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Application Information

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IPC IPC(8): A61K49/00A61K39/395A61K31/472A61K31/517A61K31/426A61K31/429C12Q1/02A61P27/02A61K31/4188A61K9/12A61K9/10A61K9/127A61K9/00
CPCA61K9/0014A61K31/14A61K31/198A61K31/277A61K31/341A61K31/343A61K31/381A61K31/4025A61K31/472A61K31/4725A61K31/496A61K31/502A61K31/517A61K31/66A61K45/06A61P3/10A61P9/10A61P27/02A61P41/00A61P43/00Y02A50/30A61F9/0017A61K9/0048A61K9/06A61K9/08A61K39/39533A61K49/00A61K2039/505A61K2039/507C07K16/2821C07K2317/92G01N33/6893G01N2333/70503G01N2333/70525G01N2800/042G01N2800/164
Inventor BURNIER, JOHNGADEK, THOMASSEMBA, CHARLES
Owner NOVARTIS AG
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