Researchers at the Broad Institute of MIT and Harvard have developed a gene-delivery vehicle that uses a human protein to efficiently cross the blood-brain barrier in mice expressing the human protein. This breakthrough could lead to more effective gene therapies for brain diseases, which currently have limited treatment options. Gene therapy has the potential to treat severe genetic brain disorders, but current delivery systems struggle to effectively cross the blood-brain barrier and deliver therapeutic cargo.
The new gene-delivery vehicle is an adeno-associated virus (AAV) that binds to the human transferrin receptor, a protein highly expressed in the blood-brain barrier in humans. This AAV successfully reached the brain in humanized mice at significantly higher levels than the currently FDA-approved AAV9 used in gene therapies for the central nervous system. The researchers demonstrated that their AAV could deliver copies of the GBA1 gene, associated with several neurological diseases, to a large fraction of brain cells, including neurons and astrocytes.
The researchers believe their AAV has the potential to treat a variety of neurodevelopmental disorders, lysosomal storage diseases, and neurodegenerative diseases caused by mutations in single genes. By targeting a human protein and demonstrating high efficiency in delivering therapeutic cargo to the brain, this new AAV offers a promising option for gene therapy in patients with brain diseases such as Rett syndrome, Huntington’s disease, and Parkinson’s disease.
The team’s approach involved screening a library of AAVs for ones that bind to the human transferrin receptor, instead of relying on traditional methods of testing in animals. By using humanized mice expressing the human transferrin receptor, the researchers were able to demonstrate the effectiveness of their AAV in crossing the blood-brain barrier and delivering therapeutic cargo to various types of brain cells. This new approach represents a significant step forward in gene therapy for brain diseases.
The gene-delivery vehicle developed by the researchers not only reached the brain at higher levels compared to existing AAVs but also showed increased accumulation in brain tissue and successful delivery of therapeutic genes. The team’s findings suggest that these AAVs could revolutionize gene therapy for central nervous system disorders and potentially improve the lives of many patients. The scalability of production, along with the potential to target the central nervous system with high efficiency, makes this new AAV a promising option for future clinical applications.
Overall, the development of this new AAV represents a crucial advancement in the field of gene therapy for brain diseases. By targeting a human protein and demonstrating superior delivery capabilities in humanized mice, the researchers have paved the way for more effective treatments for severe genetic brain disorders. With further development and optimization, these AAVs could provide a safer and more efficient option for delivering gene therapies to the brain, offering hope to patients with currently untreatable conditions.