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Engineered virus crosses blood-brain barrier to deliver gene therapy

Summary: Researchers have designed a gene therapy vehicle that efficiently crosses the blood-brain barrier in mice. This breakthrough uses a human protein to carry therapeutic genes into the brain, potentially paving the way for safer and more effective treatments for various brain diseases, including neurodevelopmental and neurodegenerative disorders.


  • A new gene delivery vehicle uses a human protein to efficiently cross the blood-brain barrier.
  • This breakthrough could lead to safer and more effective gene therapies for various brain diseases.
  • The new AAVs reached up to 71 percent of neurons and 92 percent of astrocytes in different brain regions.

Source: Expanded Institute

In an important step toward more effective gene therapies for brain diseases, researchers at the Broad Institute of MIT and Harvard have designed a gene delivery vehicle that uses a human protein to efficiently cross the blood-blood barrier. brain and deliver a gene relevant to the disease. the mouse brain expressing the human protein.

Because the vehicle binds to a well-studied protein in the blood-brain barrier, scientists say it has a good chance of working in patients.

Gene therapy could potentially treat a range of serious genetic brain disorders, for which there is currently no cure and few treatment options. But FDA-approved forms of the vehicle most commonly used to package and deliver these therapies to target cells, adeno-associated viruses (AAV), are not capable of efficiently crossing the blood-brain barrier at high levels and deliver therapeutic cargo.

This shows a virus and neurons.
For years, researchers have developed AAVs for specific applications by preparing huge AAV libraries and testing them in animals to identify the best candidates. Credit: Neuroscience News

The enormous challenge of getting therapies past this barrier – a highly selective membrane separating blood from the brain – has stalled the development of safer and more effective gene therapies for brain diseases for decades.

Now, researchers in the lab of Ben Deverman, institute scientist and senior director of vector engineering at the Broad, have developed the first published AAV that targets a human protein to reach the brains of humanized mice.

AAV binds to the human transferrin receptor, which is highly expressed in the blood-brain barrier in humans.

In a new study published in Sciencethe team showed that their AAV, when injected into the bloodstream in mice expressing a humanized transferrin receptor, crossed the brain at much higher levels than AAV used in a FDA-approved gene therapy. FDA for the central nervous system, AAV9.

It also affected a large proportion of important types of brain cells, including neurons and astrocytes.

The researchers then showed that their AAV could deliver copies of the GBA1 gene, which has been linked to Gaucher disease, dementia with Lewy bodies and Parkinson’s disease, to a large proportion of brain cells.

The scientists add that their new AAV could be a better option for treating neurodevelopmental disorders caused by mutations in a single gene, such as Rett syndrome or SHANK3 deficiency; lysosomal storage diseases like GBA1deficiency; and neurodegenerative diseases such as Huntington’s disease, prion disease, Friedreich’s ataxia, and monogenic forms of ALS and Parkinson’s disease.

“Since we came to the Broad, we have been focused on the mission of enabling gene therapies for the central nervous system,” said Deverman, lead author of the study. “If this AAV does what we think it will do in humans, based on our mouse studies, it will be much more effective than current options.”

“These AAVs have the potential to change the lives of many patients,” said Ken Chan, co-first author of the paper and leader of Deverman’s group, which has been working for nearly a year to solve gene transmission in central nervous system. decade.

The mechanism first

For years, researchers have developed AAVs for specific applications by preparing huge AAV libraries and testing them in animals to identify the best candidates. But even when this approach is successful, the candidates often don’t work in other species and the approach doesn’t provide insight into how AAVs reach their targets. This may make it difficult to translate gene therapy using these AAVs from animals to humans.

To find a delivery vehicle with a greater chance of reaching human brains, Deverman’s team took a different approach. They used a method published last year, which involves examining a library of AAVs in a test tube to detect those that bind to a specific human protein. They then test the most promising candidates in cells and mice engineered to express the protein.

As a target, the researchers chose the human transferrin receptor, which has long been the target of antibody-based therapies aimed at reaching the brain. Several of these therapies have been shown to reach the brain in humans.

The team’s screening technique identified an AAV called BI-hTFR1 that binds to the human transferrin receptor, enters human brain cells, and bypasses a human cell model of the blood-brain barrier.

“We learned a lot from in vivo “added Qin Huang, co-first author of the study and principal investigator in Deverman’s lab who helped develop the screening method to find AAVs that bind to specific protein targets. “Find one which works using a human receiver is a big step forward.”

Beyond the dish

To test AAVs in animals, researchers used mice in which the mouse gene encoding the transferrin receptor was replaced with its human equivalent. The team injected the AAVs into the bloodstream of adult mice and found significantly higher levels of AAV in the brain and spinal cord compared to mice lacking the human transferrin receptor gene, indicating that the receptor actively transported AAVs across the blood-brain barrier. .

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

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

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

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

Sonia Vallabh and Eric Minikel, two Broad researchers who are developing treatments for prion disease, are excited about the potential of AAVs to deliver brain therapies to humans.

“When we think about gene therapy for a whole-brain disease like prion disease, you need truly systemic delivery and broad biodistribution to achieve anything,” Minikel said. “Natural AAVs won’t get you anywhere. This artificial capsid opens a world of possibilities.


This work was supported by Apertura Gene Therapy, the National Institutes of Health Common Fund, the National Institute of Neurological Disorders and Stroke, and the Stanley Center for Psychiatric Research.

About this news from research in gene therapy and neurology

Author: Allessandra DiCorato
Source: Expanded Institute
Contact: Allessandra DiCorato – Broad Institute
Picture: Image is credited to Neuroscience News

Original research: Free access.
“An AAV capsid reprogrammed to bind to the human transferrin receptor mediates brain-wide gene delivery” by Ben Deverman et al. Science


An AAV capsid reprogrammed to bind to the human transferrin receptor mediates brain-wide gene delivery

The development of vehicles capable of efficiently delivering genes throughout the human central nervous system (CNS) will expand the range of treatable genetic diseases.

We designed an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds to the human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier (BBB).

BI-hTFR1 was actively transported across human brain endothelial cells and, compared to AAV9, provided 40- to 50-fold higher reporter expression in the human CNS. TFRC mouse to hit.

The increased tropism was specific to the CNS and was absent in wild-type mice.

When used to deliver GBA1whose mutations cause Gaucher disease and are linked to Parkinson’s disease, BI-hTFR1 significantly increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9.

These results establish BI-hTFR1 as a potential vector for human CNS gene therapy.

News Source : neurosciencenews.com
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