Gene therapy can be a promising therapy for both genetic and acquired brain disease. However, the limiting problem in brain gene therapy is delivery to the brain followed by regulation of the expression of the transgene. Present day gene vectors do not cross the blood-brain barrier. Now, researchers from the Broad Institute of MIT and Harvard report they have engineered a gene delivery vehicle that uses a human protein to efficiently cross the blood-brain barrier and deliver a disease-relevant gene to the brain in mice expressing the human protein. Because the vehicle binds to a well-studied protein in the blood-brain barrier, the scientists say it has a good chance of working in patients.

“It it has been tough finding AAVs that worked this well across species,” said Qin Huang, PhD, a co-first author on the study and a senior research scientist in the lab of Ben Deverman, PhD, who helped develop the screening method to find AAVs that bind specific protein targets. “Finding one that works using a human receptor is a big step forward.”

The findings are published in ScienceAn AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.”

“Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier (BBB).”

To test the AAVs in animals, the researchers used mice in which the mouse gene that encodes the transferrin receptor was replaced with its human equivalent. The team injected the AAVs into the bloodstream of adult mice and found dramatically higher levels of the AAVs in the brain and spinal cord compared to mice without the human transferrin receptor gene, indicating that the receptor was actively ferrying the AAVs across the blood-brain barrier.

The AAVs also showed 40–50 times higher accumulation in brain tissue than AAV9, which is part of an FDA-approved therapy for spinal muscular atrophy in infants but is relatively inefficient at delivering cargo to the adult brain. The new AAVs reached up to 71% of neurons and 92% of astrocytes in different regions of the brain.

In work led by research scientist Jason Wu, PhD, Deverman’s team also used the AAVs to deliver healthy copies of the human GBA1 gene, which is mutated in several neurological conditions. The new AAVs delivered 30 times more copies of the GBA1 gene than AAV9 in mice and were delivered throughout the brain.

The team reported that the new AAVs are ideal for gene therapy because they target a human protein and have similar production and purification yields as AAV9 using scalable manufacturing methods. A biotech company co-founded by Deverman, Apertura Gene Therapy, is already developing new therapies using the AAVs to target the central nervous system.

With further development, the researchers believe it’s possible to improve the gene-delivery efficiency of their AAVs to the central nervous system, decrease their accumulation in the liver, and avoid inactivation by antibodies in some patients.

“When we think about gene therapy for a whole-brain disease like prion disease, you need really systemic delivery and broad biodistribution in order to achieve anything,” said Eric Minikel, PhD, a researcher at the Broad. “Naturally occurring AAVs just aren’t going to get you anywhere. This engineered capsid opens up a world of possibilities.”

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