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Methods and Compositions for Treating Conditions of the Eye

a technology of compositions and ocular conditions, applied in the field of photodynamic therapy, can solve the problems of not meeting the criteria for laser photocoagulation therapy, the majority of patients with neovascular amd do not meet the etiology and pathogenesis of disease, and the etiology of disease, etc., to achieve the effect of reducing or delaying the recurrence, increasing the selectivity of cnv, and improving treatment efficacy

Inactive Publication Date: 2009-11-19
MASSACHUSETTS EYE & EAR INFARY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a more effective and selective method for treating ocular conditions associated with unwanted choroidal neovasculature (CNV) using PDT-based methods. The method involves administering an anti-angiogenesis factor (AAF) to a mammal prior to the administration of a photosensitizer (PDT dye) and then irradiating the CNV with laser light. The AAF enhances the selectivity of the PDT by occluding the CNV while sparing surrounding blood vessels, tissues, and retinal cells. The method also reduces the recurrence of CNV and can be used in combination with other anti-angiogenic factors such as angiostatin, endostatin, and pigment epithelium-derived growth factor.

Problems solved by technology

Although clinicopathologic descriptions have been made, little is understood about the etiology and pathogenesis of the disease.
Currently there is no treatment for dry AMD.
Unfortunately, the majority of patients with neovascular AMD do not meet the criteria for laser photocoagulation therapy.
In addition, laser photocoagulation relies on thermal damage to the CNV tissue, which damages the overlying neurosensory retina with consequent loss of visual function.
Laser photocoagulation also is plagued by recurrences that occur in approximately 50% of cases.
Increasing photosensitizer or light doses do not appear to prevent this recurrence, and can even lead to undesired non-selective damage to retinal vessels (Miller et al.
The necessity for repeated PDT treatments can nevertheless be expected to lead to cumulative damage to the retinal pigment epithelium (RPE) and choriocapillaris, which may lead to progressive treatment-related vision loss.

Method used

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  • Methods and Compositions for Treating Conditions of the Eye
  • Methods and Compositions for Treating Conditions of the Eye
  • Methods and Compositions for Treating Conditions of the Eye

Examples

Experimental program
Comparison scheme
Effect test

example 1

Anti-Angiogenesis Factor Potentiates the Effect of PDT on Endothelial Cells

[0073]Experiments were performed to determine whether the cytotoxicity resulting from PDT can be potentiated by the addition of an anti-angiogenesis factor. Cells of interest were treated by PDT either alone or in combination with an anti-angiogenesis factor and the effect on cytotoxicity of the PDT assessed via a cell proliferation assay.

[0074]Bovine retinal capillary endothelial (BRCE) cells (from Patricia A. D'Amore, Schepens Eye Research Institute, Boston, Mass.) and Human retinal pigment epithelial (RPE) cells (from Anthony P. Adamis, Massachusetts Eye & Ear Infirmary, Boston, Mass.) were grown at 37° C., 5% CO2 in Dulbecco's modified Eagle's medium (DMEM; Sigma, St. Louis, Mo.), 5% heat-inactivated fetal bovine serum (FBS, Gibco, Grand Island, N.Y.), supplemented with L-glutamine, penicillin, and streptomycin (Gibco Grand Island, N.Y.). Lutetium Texaphyrin (Lu-Tex) was obtained from Alcon Laboratories, ...

example 2

Cellular Morphology Following PDT with Anti-Angiogenic Factor

[0080]Experiments were performed to establish how PDT effects the cellular morphology of BRCE and RPE cells. The cells were treated and exposed to PDT either alone or in combination with angiostatin as described in Example 1. Although cells appeared severely damaged immediately after PDT, subsequent recovery occurred in certain circumstances. One week after PDT, some cells disappeared while those that remained regained their spindle shape and their ability to attach.

[0081]In BRCE cells that were first primed with angiostatin followed by PDT, widespread and massive cell death was observed at one week. Only remnants of cells and densely refractive bodies of dying cells were observed floating in the medium. Particles were recovered and placed in fresh complete media but none showed any sign of reattachment or proliferation onto a new dish. The combination of angiostatin and Lu-Tex / PDT, therefore, appears to be lethal to BRCE ...

example 3

Caspase 3-Like (DEVD-ase) Activation in BRCE and RPE Following PDT

[0083]In order to investigate the role of apoptosis in Lu-Tex / PDT mediated cell death in BRCE and RPE, the activation of Caspase 3-like (DEVD-ase) protease, a hallmark of apoptosis (Nicholson (1997) TIBS 22: 299-306), was monitored. The kinetics of activation were measured spectrofluorometrically by assaying the hydrolysis of a substrate that can be cleaved only by the caspase 3-like protease family members.

[0084]Various times after Lu-Tex / PDT, 106 cells were collected by centrifugation, and the washed cell pellet resuspended in 500 μl of ice-cold lysis buffer (pH 7.5) containing 10 mM Tris, 130 mM NaCl, 1% Triton X-100, 10 mM NaF, 10 mM NaPi, 10 mM NaPPi, 16 μg / ml benzamidine, 10 μg / ml phenanthroline, 10 μg / ml aprotinin, 10 μg / ml leupeptin, 10 μg / ml pepstatin and 4 mM 4(2-aminoethyl)-benzene-sulfanyl fluoride hydrochloride (AEBSF). Cellular lysates were stored in aliquots at −84° C. for later protease activity assay ...

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Abstract

Provided are methods and compositions for the photodynamic therapy (PDT) of ocular conditions characterized by the presence of unwanted choroidal neovasculature, for example, neovascular age-related macular degeneration. The selectivity and sensitivity of the PDT method can be enhanced by combining the PDT with an anti-angiogenesis factor, for example, angiostatin or endostatin, or with an apoptosis-modulating factor. Furthermore, the selectivity and sensitivity of the PDT may be further enhanced by coupling a targeting moiety to the photosensitizer so as to target the photosensitizer to choroidal neovasculature.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 60 / 181,641, filed Feb. 10, 2000, the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates generally to photodynamic therapy-based methods and compositions for treating ocular conditions and, more specifically, the invention relates to photodynamic therapy-based methods and compositions for treating ocular conditions characterized by unwanted choroidal neovasculature.BACKGROUND[0003]Choroidal neovascularization can lead to hemorrhage and fibrosis, with resulting visual loss in a number of conditions of the eye, including, for example, age-related macular degeneration, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, and certain inflammatory diseases. One of the disorders, namely, age-related macular degeneration (AMD), is the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/10A61F9/007A61D7/00A61K31/197A61K31/352A61K31/409A61K31/655A61K38/00A61K38/48A61K41/00A61K45/06A61K47/48A61N5/06A61P27/02
CPCA61K38/10A61K38/484A61K41/0057A61K41/0076A61K41/0071A61K47/48561A61N5/062A61K47/48246A61K45/06A61K2300/00A61K47/64A61K47/6849A61P27/02A61P27/06A61P43/00
Inventor MILLER, JOAN W.GRAGOUDAS, EVANGELOS S.RENNO, REEM Z.
Owner MASSACHUSETTS EYE & EAR INFARY
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