In a significant scientific breakthrough, researchers from the Broad Institute of MIT and Harvard have engineered a gene therapy delivery vehicle that efficiently crosses the blood-brain barrier in mice. This breakthrough holds great potential for the development of safer and more effective treatments for various brain diseases, including neurodevelopmental and neurodegenerative disorders.

The researchers have successfully utilized a human protein to transport therapeutic genes into the brain, a feat that could open doors for cutting-edge gene therapies. By binding to the human transferrin receptor, a protein found in the blood-brain barrier, the gene delivery vehicle demonstrates a high likelihood of working effectively in human patients.

Adeno-associated viruses (AAVs) are commonly used as vehicles to deliver gene therapies to target cells. However, currently approved forms of AAVs struggle to efficiently cross the blood-brain barrier in significant numbers. Overcoming this challenge has been a major obstacle in the development of safer and more effective gene therapies for brain diseases.

The breakthrough AAV developed by the researchers has shown remarkable results in reaching the brain. In mice expressing the human transferrin receptor, the new vehicle crossed into the brain at much higher levels compared to the FDA-approved AAV9 used in central nervous system gene therapies. Notably, it reached up to 71 percent of neurons and 92 percent of astrocytes in various regions of the brain.

The team demonstrated the potential of their AAV by successfully delivering the disease-relevant GBA1 gene to a large fraction of brain cells. The GBA1 gene is associated with various brain disorders, including Gaucher's disease, Lewy body dementia, and Parkinson's disease. This suggests that the new AAV could be an effective treatment option for these conditions, as well as other genetic brain disorders like Rett syndrome, SHANK3 deficiency, lysosomal storage diseases, and neurodegenerative diseases such as Huntington's disease, prion disease, Friedreich's ataxia, ALS, and Parkinson's disease.

Ben Deverman, the senior author of the study, expressed optimism about the potential impact of this new therapy, stating, "If this AAV does what we think it will in humans based on our mouse studies, it will be so much more effective than current options." The team believes that these AAVs have the power to significantly improve the lives of many patients.

The researchers used a novel approach to identify their delivery vehicle, screening a library of AAVs for ones that bind to the human transferrin receptor. By utilizing a human protein target, they aim to enhance the compatibility and effectiveness of the therapy in human patients.

The new AAVs have already shown exceptional promise in animal models, surpassing the capabilities of previously used AAVs. The researchers believe that with further development, they can enhance the delivery efficiency of their AAVs to the central nervous system. They also aim to decrease accumulation in non-target tissues and overcome potential challenges posed by antibodies in certain patients.

This breakthrough has attracted the attention of both scientists and industry. Apertura Gene Therapy, a company co-founded by Ben Deverman, is already working on developing therapies using the AAVs to target the central nervous system. Researchers Sonia Vallabh and Eric Minikel, who are focused on treatments for prion disease, express excitement over the potential of the AAVs to deliver brain therapies in humans.

The groundbreaking research was supported by Apertura Gene Therapy, the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Stanley Center for Psychiatric Research. As further studies and advancements are made, the potential for safer and more effective gene therapies for a wide range of brain diseases becomes increasingly tangible.