Evaluation of a Brain Endothelium Transmembrane Protein as a Therapeutic Target for Drug Delivery across the Blood Brain Barrier

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Neurological diseases, especially cancers and infections of the brain, present a major challenge to health care providers and drug developers alike. Most therapeutics cannot cross the blood brain barrier (BBB), which maintains the optimal environment for neuronal function. Current efforts in therapeutics focus on developing drug-delivery systems and targeted drugs that allow therapeutics to cross the BBB in a safe and effective manner. Vertex realizes the potential of alternate and emerging drug modalities and, importantly, the possibilities for targeted drug delivery. With the growing interest in neurological disorders in mind, Vertex aims to explore new materials that provide penetration of the BBB to its molecules, first as a tool for early research, and ultimately as a platform for approved treatments of disease. A recently identified transmembrane protein that is selectively expressed on the brain endothelium and acts as a regulator of the transport of molecules across the BBB is attractive to Vertex as a potential target for delivering medicines specifically to the brain. Identifying a peptide that binds specifically to this transmembrane protein might provide an anchor for the development of materials for targeted drug delivery. Phage display represents one approach that has been leveraged to discover molecules (peptides in this case) that recognize cell-surface receptors. Contrary to traditional phage display that allows for encoding and selection of peptide-based libraries only, the Derda group at the University of Alberta developed methodology for chemical post-translational modification of phage-displayed libraries to introduce unnatural moieties beyond traditional 20 amino acids. From such hybrid libraries one can rapidly identify ligands that target brain specific transmembrane proteins with high specificity and affinity. This project will focus on the identification of ligands that bind selectively to brain specific transmembrane proteins, the functionalization of materials with these ligands, and the evaluation of these materials for facilitating increased uptake from the microvasculature to the brain parenchyma.