Hijacking small hydrophobic protein transport to deliver therapeutic agents to the central nervous system

ongoing

Neurological disorders affect over 540 million individuals in Europe alone, yet effective treatments are limited, primarily due to the challenge of delivering therapeutic compounds across the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). This project aims to develop a novel, virus-inspired technology that utilizes small hydrophobic (SH) proteins, derived from the neurotropic mumps virus to shuttle CNS-active molecules across the BCSFB via the GPR125 receptor. This innovative approach will allow for the effective delivery of therapeutic agents and avoid issues surrounding chemical modification and viral vector packaging of drugs. Building on promising preliminary data, where an SH protein conjugated to Exendin-4 significantly reduced appetite in mice, this project will focus on understanding transport mechanisms of SH-conjugated molecules into the brain. The research will be divided into three work packages (WPs). WP1 will investigate the mechanism of SH-GPR125 transport in vitro using choroid plexus cells and advanced imaging techniques. WP2 will examine the pharmacokinetics and bioavailability of SH-Silicon Rhodamine (SiR) in vivo, determining its uptake in GPR125 knockout and wild-type mice. WP3 will assess the efficacy of SH-enkephalin, a therapeutic peptide targeting the mu-opioid receptor, in an acute pain model, testing its ability to reduce pain perception in mice. This project offers a transformative approach to CNS drug delivery, with the potential to revolutionize treatment for a range of neurological disorders, including Alzheimer’s, Parkinson’s, and ALS. By leveraging the natural ability of neurotropic viruses to cross the BCSFB, we propose a method that bypasses current limitations in CNS drug delivery. The outcomes of this research will provide a foundation for future clinical applications, potentially leading to new therapies that address the urgent unmet medical needs posed by neurological disorders.