Enhancing Gene Therapy Delivery to the Brain via Human Blood-Brain Barrier Receptors

This project focuses on a novel gene therapy strategy aimed at addressing the genetic roots of FA, offering new hope for effective treatments. Gene therapy involves using specially designed delivery vectors, to deliver therapeutic genes directly to affected areas in the brain. The primary hurdle in treating brain disorders like FA is the blood-brain barrier (BBB), a natural defense mechanism that prevents most drugs from entering the brain. Dr Lin is using AAV delivery vectors because of their unique ability to cross this barrier. However, directing these vectors precisely and efficiently to the areas where they are needed remains a significant challenge. With support from a previous FARA Postdoctoral Fellowship, Dr Lin has embarked on an innovative approach that involves modifying the AAVs so they can more effectively target and cross the BBB. The focus is on a specific receptor, carbonic anhydrase IV (CA4), found abundantly within the BBB and the cerebellum. Through this research, Dr Lin and his mentor at Caltech, Dr Viviana Gradinaru, have successfully engineered AAV variants that demonstrate an enhanced ability to target CA4, thereby improving their delivery efficiency to the cerebellum. Moving forward, this work targets further refinement of AAV vectors, aiming to boost their targeting precision and efficiency for gene delivery to the brain. This involves an in-depth exploration of how these vectors interact with the blood-brain barrier (BBB), specifically focusing on enhancing their ability to engage with the CA4 receptor. Such enhancements are crucial for improving delivery directly to the cerebellum, a key area affected in FA. A critical component of this approach is the extensive screening of AAV libraries against models of the human BBB and brain organoids. This screening aims to identify the most effective vectors with dual functions, crossing the BBB and achieving targeted delivery to the cerebellum. Success in this area could revolutionize FA treatments.