The innovative use of a synthetic peptide to modulate epithelial cell-cell interactions is proposed for the augmentation of drug- or gene-based therapeutic interventions. Cell monolayers are a major obstacle to delivering drugs to selected locations throughout the body. Transient access to these compartments would provide an additional means to treat debilitating and life-threatening disorders. Recently Nacelle Therapeutics, Inc. identified a small group of ion channel-forming peptides that transiently reduces electrical resistance (a measure of barrier integrity) across a variety of transformed epithelial cell monolayers. This observation was outside of the targeted outcome, but its therapeutic potential was immediately recognized. Preliminary experiments indicated that peptide exposure increased the permeability of the paracellular pathway to small (<20 kDa) but not large dextrans for a short period of time. We now propose to explore the potential applications of these peptides as short-acting modulators of epithelial barriers in the eye. It has long been recognized that delivery of instilled hydrophilic or larger molecular weight drugs into the corneal stroma as well as interior portions of the eye is difficult due in part to the highly-resistive outer epithelial layer(s). For example, the drug vancomycin is extremely hydrophilic and must be administered to the eye by injection. We hypothesize that inclusion of NC-1059 with this or other hydrophilic antibiotics should greatly enhance ophthalmic drug delivery. Over the next year, we will measure transport of fluorescently-labeled antibiotics across isolated cornea and sclera-conjuntiva in the presence and absence of our highest potency peptide, NC-1059, as well as several control sequences. The outcomes of these studies will identify specific target tissues in the eye that can be therapeutically modulated by this peptide as well as the areas of the eye that can be accessed using this approach. Both sequential and combined administration schedules will be assessed. Solution formulations with different molar ratio formulations will be investigated for both increased efficacy as well as stability during storage. These proof-of-concept studies are directed toward the treatment of acute infections of the eye through the instillation of drugs in drops rather than the current approach using injections.
Thesaurus Terms: drug design /synthesis /production, drug screening /evaluation, epithelium, eye, membrane permeability, peptide antibiotic, combination chemotherapy, conjunctiva, cornea, corneal epithelium, dosage, eye disorder chemotherapy, eye infection, eye pharmacology, pharmacokinetics, sclera, topical drug application, vancomycin MDCK cell, confocal scanning microscopy, fluorescence, laboratory rabbit, tissue /cell culture, tissue /cell preparation
