Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells

Abstract

A treatment solution used to prevent posterior capsular opacification is applied or introduced into the lens capsular bag before, during, or after cataract surgery. The treatment solution may also be applied to an intraocular lens prior to surgery. The treatment solution comprises an ion transport mechanism interference agent, which either alone or in combination with other treatment agents such as an osmotic stress agent and an agent to establish a suitable pH, selectively induces detachment and / or death of lens epithelial cells such that posterior capsular opacification is prevented. While the ion transport mechanism interference agent is capable of interfering with the cellular mechanisms and cell ion distribution of a broad range of cells, a concentration of agent is selected such that the treatment solution interferes selectively with the cellular mechanisms of lens epithelial cells while leaving other ocular cells substantially unharmed. The treatment solution selectively induces cellular death and / or detachment of lens epithelial cells while other ocular cells and tissue remain substantially unharmed and without lengthy preoperative pre-treatment.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 11 / 015,532, which was filed on Dec. 17, 2004, and which is set to issue on Jan. 25, 2011 as U.S. Pat. No. 7,875,270. U.S. patent application Ser. No. 11 / 015,532 is a continuation-in-part of U.S. patent application Ser. No. 10 / 244,878 filed Sep. 17, 2002. U.S. patent application Ser. Nos. 11 / 015,532 and 10 / 244,878 are herein incorporated by reference in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]N / ATECHNICAL FIELD[0003]The present invention relates to novel treatment solutions and methods comprising an ion transport mechanism interference agent, alone or in combination with other agents, used to prevent posterior capsular opacification by selectively inducing detachment and / or cell death of lens epithelial cells without damaging other ocular cells and tissue and without lengthy preoperative treatment.BACKGROUND OF THE INVENTION...

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[0047]In one aspect, the ocular treatment solutions and methods of the present invention prevent PCO by inducing substantially greater incidence of detachment of the LECs from their substrates or membranes and / or cell death than other ocular cells such as corneal endothelial cells (CEDCs) and retinal pigmented epithelial cells (RPECs) via an ion transport mechanism interference agent. Therefore, a significant advantage of the present invention is that treatment with the agents of the present invention prevents PCO by allowing for removal from the lens capsular bag of a substantial percentage of LECs, while other ocular cells and tissue are not significantly harmed.

[0048]The ion transport mechanism interference agent is an agent capable of interfering, either directly or indirectly, with intracellular, extracellular and / or intercellular mechanisms that regulate the flow of ions and water across or within the cellular membrane of a lens epithelial cell. The ion transport mechanism interference agent interferes with normal cellular ion distribution mechanisms and consequently the functions of cells. The ion transport mechanism interference agent of the present invention, either alone or in combination with other agents, disturbs the normal distribution of LEC cell ions and thereby selectively induces, either directly or indirectly, LEC detachment and / or death to prevent PCO. A concentration of the agent is selected such that the treatment solution interferes with ion transport mechanisms of LECs causing cellular volume changes, detachment and / or death of LECs, but does not substantially interfere with ion transport mechanisms of other ocular cells. While LECs may be easily removed from the lens capsular bag due to cell detachment and / or death, other ocular cells remain substantially unharmed.

[0049]The ion transport mechanism interference agent is capable of interfering with one or more of the following cellular mechanisms in an LEC: (1) co-transport mechanisms (for example, K+—Cl− co-transport, Na+—Cl− co-transport, Na+—K+-2Cl− co-transport and amino acid transport); (2) the sodium pump; (3) ion exchanges (for example, functionally coupled Na+—H+ and Cl−—HCO3− exchanges; functionally coupled K+—H+ and Cl−—HCO3− exchange, Cl−—Cl− exchange, Ca2+—Na+ exchange); and (4) ion channels (for example, potassium channels, chloride channels, volume-sensitive organic osmolyte and anion channel (VSOAC), pore-forming proteins and peptides and other anion channels). The ion transport mechanism interference agent may activate or inhibit either directly or indirectly these cellular mechanisms.

[0050]In hypotonic media, vertebrate cells initially swell by osmotic water equilibration but subsequently regulate their volume by a net loss of KCl and a concomitant loss of cell water to restore normal cell volume. Cell swelling activates transport pathways that result in the net efflux of potassium, chloride and organic osmolytes. The ion transport mechanisms activated during RVD in various cell types involve conductive K+ and Cl− channels (separate, conductive K+ and Cl− transport pathways), K+—Cl− co-transport, and functionally coupled K+—H+ and Cl−—HCO3− exchange. For example, potassium and chloride are lost from the cell primarily through activation of the K+—Cl− co-transport or through separate potassium and anion channels.

[0051]In contrast, in hypertonic media, vertebrate cells initially shrink by osmotic water equilibration but subsequently regulate their volume by a net gain of KCl and a concomitant uptake of cell water to restore normal cell volume. Cell shrinkage activates transport pathways that result in the net influx of chloride, sodium, and potassium. The ion transport mechanisms activated during RVI in various cell types involve Na+—Cl− or Na+—K+-2Cl− co-transport, and functionally coupled Na+—H+ and Cl−—HCO3 exchange.

[0052]Examples of ion transport mechanism interference agents include, but are not limited to:

Problems solved by technology

This interference may cause cells to shrink and / or swell, resulting in cell detachment and / or death.

The ion transport mechanism interference agents may themselves induce cellular volume changes and / or cell detachment and / or death of LECs or may sensitize LECs such that the LECs are rendered incapable of sufficiently responding to an additional agent that causes osmotic stress, selectively detaching and / or killing the LEC and preventing PCO.

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