Engineered AAV Efficiently Crosses Blood-Brain Barrier in Mice

Researchers at the Broad Institute of MIT and Harvard have engineered an adeno-associated virus (AAV) that can efficiently cross the blood-brain barrier and deliver therapeutic genes to the brain in mice. This AAV binds to the human transferrin receptor, a protein highly expressed at the blood-brain barrier.

Overcoming the blood-brain barrier has been a major obstacle in developing gene therapies for neurological diseases like Parkinson's, Huntington's, and ALS. Current FDA-approved AAVs cannot efficiently penetrate this protective membrane separating blood from brain tissue.

The new AAV, called BI-hTFR1, was designed using a novel screening approach that identifies AAVs capable of binding to specific human protein targets. After screening for binding to the transferrin receptor, the top candidates were tested in human cell models and humanized mice engineered to express the human transferrin receptor gene.

When injected intravenously into these mice, BI-hTFR1 crossed the blood-brain barrier at dramatically higher levels compared to mice without the human receptor gene. It accumulated in brain tissue at 40-50 times higher levels than AAV9, the vector used in an FDA-approved gene therapy.

Remarkably, BI-hTFR1 reached up to 71% of neurons and 92% of astrocytes across different brain regions. It also delivered over 30 times more copies of a therapeutic gene (GBA1) throughout the brain compared to AAV9 when used as a gene delivery vehicle.

The researchers believe BI-hTFR1 has a high chance of working in human patients since it targets a well-studied human protein. It could enable safer, more effective gene therapies for a range of neurodevelopmental, neurodegenerative, and lysosomal storage diseases caused by single gene mutations.

"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," said Ben Deverman, senior author on the paper published in Science.