Engineered Adeno-Associated Virus Successfully Delivers Genes Across Blood-Brain Barrier in Mice

Gene therapy presents a promising solution for various brain diseases, both inherited and acquired. However, the primary challenge lies in effectively delivering genes to the brain and regulating the expression of the transgene. Existing gene vectors face difficulty in crossing the blood-brain barrier. Researchers from the Broad Institute of MIT and Harvard have recently developed an engineered gene delivery vehicle that utilizes a human protein to efficiently traverse the blood-brain barrier and transport a gene relevant to disease into the brains of mice expressing the human protein. This breakthrough offers new hope for patients.The engineered adeno-associated virus (V) capsid, BI-hTFR1, targets the human transferrin receptor (TfR1) present on the blood-brain barrier. By replacing the mouse TfR1 gene with its human counterpart in mice, the team observed significantly higher levels of Vs in the brain and spinal cord upon injection into the bloodstream of adult mice. Compared to the FDA-approved V9, the new Vs demonstrated 4050 times greater accumulation in brain tissue, reaching a substantial percentage of neurons and astrocytes in various brain regions.

Research led by Jason Wu, PhD, also utilized the new Vs to deliver healthy copies of the human GBA1 gene, known to be mutated in several neurological disorders. The Vs successfully delivered significantly more copies of the GBA1 gene throughout the brain compared to V9. Additionally, these novel Vs exhibit characteristics ideal for gene therapy, such as targeting a human protein and maintaining efficient production and purification yields, similar to V9, using scalable manufacturing methods.

Furthermore, the development of these Vs opens up opportunities for new therapies targeting the central nervous system. Apertura Gene Therapy, a biotech company co-founded by Ben Deverman, PhD, is already working on developing innovative treatments utilizing the Vs. The researchers envision enhancing the gene-delivery efficiency of the Vs to the central nervous system, reducing their accumulation in the liver, and preventing inactivation by antibodies in certain patients.

Looking ahead, the team aims to refine the engineered capsid for systemic delivery and broad biodistribution in treating whole-brain diseases like prion disease. The engineered Vs offer a promising avenue for advancing gene therapy in the realm of brain-related conditions, providing new possibilities for effective treatment strategies.