According to the latest issue of the journal "Science," a team from the Massachusetts Institute of Technology and the Broad Institute of Harvard University has designed a gene delivery vehicle that can effectively utilize human proteins to cross the blood-brain barrier. This vehicle successfully delivered disease-related genes to the entire brain of humanized mice, marking a significant step towards developing more effective gene therapies for brain diseases.
Gene therapy holds promise for treating a range of severe genetic brain disorders that are currently incurable with limited treatment options. However, the most commonly used vector approved by the Food and Drug Administration (FDA) for packaging and delivering these therapeutic drugs to target cells, adeno-associated virus (AAV), has been ineffective in crossing the blood-brain barrier. For decades, overcoming this barrier has posed a major challenge, hindering the development of safer and more effective gene therapies for brain diseases.
The team at the Broad Institute has now designed the first AAV that targets human proteins and reaches the brains of humanized mice. This AAV may be a better choice for treating neurodevelopmental disorders caused by single-gene mutations. In animal tests, mice genes encoding the transferrin receptor were first replaced with their human counterparts. Subsequently, researchers injected the AAV into the bloodstream of adult mice and found significantly higher levels of AAV in the brains and spinal cords compared to mice without the human transferrin receptor gene. This indicates that the receptor actively transports the AAV across the blood-brain barrier.
The accumulation of the new AAV in brain tissue is 40-50 times higher than AAV9, which is part of an FDA-approved therapy for infantile spinal muscular atrophy. The new AAV covers up to 71% of neurons and 92% of astrocytes in different regions of the brain. The copy number of the GBA1 gene (associated with Gaucher disease, Lewy body dementia, and Parkinson's disease) delivered in mice is 30 times higher than AAV9 and reaches most cells throughout the brain.
This suggests that the levels of the new AAV entering the brain are significantly higher than those used in FDA-approved gene therapies, and it reaches most major types of brain cells.
