Lkktet and/or lkktnt peptide compositions and methods for treating or preventing tissue deterioration, injury or damage

This application claims the benefit of U.S. Provisional Application No. 60/691,261, filed Jun. 17, 2005 and U.S. Provisional Application No. 60/776,947, filed Feb. 28, 2006.

1. Field of the Invention

The present invention relates to the field of LKKTET and/or LKKTNT compositions and methods.

2. Description of the Background Art

Thymosin beta 4 initially was identified as a protein that is up-regulated during endothelial cell migration and differentiation in vitro. Thymosin beta 4 was originally isolated from the thymus and is a 43 amino acid, 4.9 kDa ubiquitous polypeptide identified in a variety of tissues. Several roles have been ascribed to this protein including a role in a endothelial cell differentiation and migration, T cell differentiation, actin sequestration, vascularization and wound healing.

Many Tβ4 isoforms have been identified and have about 70%, or about 75%, or about 80% or more homology to the known amino acid sequence of Tβ4. Such isoforms include, for example, Tβ4^ala, Tβ9, Tβ10, Tβ11, Tβ12, Tβ13, Tβ14 and Tβ15. Similar to Tβ4, the Tβ10 and Tβ15 isoforms have been shown to sequester actin. Tβ4, Tβ10 and Tβ15, as well as these other isoforms share an amino acid sequence, LKKTET or LKKTNT, that appears to be involved in mediating actin sequestration or binding. Although not wishing to be bound by any particular theory, the activity of peptide agents as described herein may be due, at least in part, to the anti-inflammatory activity of such agents. Tβ4 also can modulate actin polymerization (e.g. β-thymosins appear to depolymerize F-actin by sequestering free G-actin). Tβ4\'s ability to modulate actin polymerization may be due to its ability to bind to or sequester actin via the LKKTET or LKKTNT sequence.

There remains a need in the art for LKKTET and/or LKKTNT compositions and methods.

According to one embodiment, a composition for administration to skin tissue of a subject, comprises a peptide agent comprising amino acid sequence LKKTET or LKKTNT, a conservative variant thereof, or a stimulating agent that stimulates production in said tissue of an LKKTET or LKKTNT peptide, or a conservative variant thereof, the composition further comprising a quaternary ammonium salt and a topical carrier for application to skin tissue of said subject.

According to another embodiment, a pharmaceutical, ophthalmic or cosmetic combination comprises a peptide agent comprising amino acid sequence LKKTET or LKKTNT, a conservative variant thereof, or a stimulating agent that stimulates production of an LKKTET or LKKTNT peptide, or a conservative variant thereof, the combination further comprising a quaternary ammonium salt, wherein said agent and said salt can be administered to a subject separately or together.

According to a further embodiment, a method of treatment for treating, preventing, inhibiting or reducing tissue deterioration, injury or damage resulting from administration of a quaternary ammonium salt to a subject, comprises administering said quaternary ammonium salt to said subject, and administering to said subject a peptide agent comprising amino acid sequence LKKTET or LKKTNT, a conservative variant thereof, or a stimulating agent that stimulates in said tissue production of an LKKTET or LKKTNT peptide, or a conservative variant thereof.

Many compositions that are administered to subjects for various purposes contain one or more ingredients that may cause injury to the subject.

For example, preservatives such as benzalkonium chloride (BAK), which are present in many ophthalmic and cosmetic products, may cause surface irritation and/or injury when the product is administered. Symptoms may include redness and discomfort.

There is a significant and growing problem with ocular surface irritation and apoptosis with chronic use of eye drops containing quaternary ammonium salts such as BAK. Patients often develop symptoms such as redness and general eye discomfort. A peptide agent in accordance with the present invention, such as thymosin beta 4 (Tβ4), can be utilized to treat or prevent damage or injury to eye tissue when administered to a subject in combination with contacting the eye tissue with a quaternary ammonium salt such as BAK.

Examples of quaternary ammonium salts to which the present invention may be applicable include BAK, cetrimide, benzoxonium chloride, and the like.

According to one embodiment, the peptide agent is administered together with the quaternary ammonium salt such as BAK as part of the same formulation, e.g., as an additive to a formulation containing BAK or other quaternary ammonium salt. Quaternary ammonium salts such as BAK are ingredients commonly used as preservatives in many ocular solutions, such as glaucoma eye drops.