BIGH3-related corneal dystrophies are a group of potentially blinding inherited corneal disorders that have been attributed to more than 30 missense mutations of BIGH3 gene in 5q3l of humans. These dystrophies are characterized by stromal amyloid and/or non-amyloid deposits, and painful recurrent corneal erosions due to poor epithelial adhesions. Corneal transplantation or phototherapeutic keratectomy (PTK) is often needed to remove corneal opacities and scars. These therapeutic options offer only temporary relief and cannot prevent recurrences, thereby necessitating other non-invasive yet effective, alternative treatments In this proposal, we intend to employ novel synthetic peptides, known as Meptides (N-methylated peptide), to prevent the abnormal amyloid fibril aggregations in BIGHS-related corneal dystrophies. The therapeutic potential of meptides has been demonstrated in Alzheimer's disease. Meptides with their relatively small size and sequence-specific inhibition of amyloidogenic region offer greater advantages over other therapeutic options such as amyloid-specific antibody or nonspecific amyloid-interfering compounds. We have identified and synthesized two meptides specifically targeting one of the amyloidogenic regions of BIGH3. Our preliminary studies with Thioflavin T fluorescence assay and electron microscopy demonstrated that these meptides successfully suppressed amyloid fibril formation in vitro. We will further modify the compositions of meptides for optimal inhibition of amyloid aggregations and investigate their bioavailability, potential toxicities and immune response in corneal tissues with cultured corneal cells, organ cultures and animal models. The knowledge thus learned from meptide-mediated perturbation of protein aggregations should facilitate further understanding of the abnormal protein aggregations in BIGHS-related corneal dystrophies and serve as a foundation for developing future therapies for BIGHS-related corneal dystrophies and other conformational diseases related to protein misfolding. ? ? ? ?
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