an engineered gene-delivery vehicle to efficiently cross the blood-brain barrier and deliver a disease-relevant gene to the brain in mice expressing the human protein. This advancement holds promise for potential use in patients, as the vehicle binds to a well-studied protein in the blood-brain barrier.blood-brain barrier to reach the brain. This limitation has hindered the potential of gene therapy for treating brain disorders.
However, scientists have developed a new vehicle that can effectively transport a disease-relevant gene to the brain in mice expressing a specific human protein. The vehicle binds to a well-studied protein in the blood-brain barrier, which increases the likelihood of its success in patients.
This advancement is significant because it offers hope for the treatment of severe genetic brain disorders that currently lack effective cures or treatment options. The new vehicle could potentially overcome the previous limitations of existing FDA-approved adeno-associated viruses (AAVs) and enable gene therapy to target cells in the brain more efficiently.The blood-brain barrier poses a major obstacle to delivering therapeutic cargo at high levels. This barrier, which acts as a selective membrane separating the blood from the brain, has hindered the development of safer and more effective gene therapies for brain diseases for many years.
In a recent study, researchers in the lab of Ben Deverman, an institute scientist and senior director of vector engineering at the Broad, have successfully engineered the first AAV that targets a human protein to reach the brain in humanized mice. Specifically, the AAV binds to the human transferrin receptor, a protein that is highly expressed in the blood-brain barrier in humans.In a recent Science study, researchers found that their AAV, when injected into mice with a humanized transferrin receptor, entered the brain at higher levels than the FDA-approved AAV9 used in gene therapy for the central nervous system. Additionally, it reached various important brain cell types such as neurons and astrocytes. The researchers also demonstrated that their AAV successfully delivered copies of the GBA1 gene, which is associated with Gaucher’s disease, Lewy body dementia, and Parkinson’s disease, to a large number of cells throughout the brain.The scientists suggest that the new AAV they have developed could be a better option for treating neurodevelopmental disorders caused by mutations in a single gene, such as Rett syndrome or SHANK3 deficiency. It may also be effective in treating lysosomal storage diseases like GBA1 deficiency, as well as neurodegenerative diseases such as Huntington’s disease, prion disease, Friedreich’s ataxia, and single-gene forms of ALS and Parkinson’s disease.
Deverman, the senior author of the study, stated, “Since we came to the Broad we’ve been focused on the mission of enabling gene therapies for the central nervous system. If this AAV does what we think it will in humans based on our mouse studies, it will be a significant development.”
“The potential of these AAVs to improve patient lives is significant,” stated Ken Chan, a co-first author of the paper and a group leader at Deverman’s lab. Chan has dedicated almost ten years to resolving gene delivery to the central nervous system.
Priority on Mechanism
For numerous years, scientists created AAVs for specific purposes by creating extensive AAV libraries and testing them on animals to identify the top choices. However, even when this method is successful, the chosen options often do not function in other species, and it does not offer insight into how.The AAVs struggle to effectively deliver gene therapy from animals to humans because they have difficulty reaching their intended targets. In order to find a better vehicle for delivering gene therapy to the brain in humans, Deverman’s team decided to change their approach. They utilized a method that they had previously published, where they screened a library of AAVs in a test tube to identify ones that bind to a specific human protein. The most promising candidates were then tested in cells and mice that had been modified to express the protein. The researchers selected the human transferrin receptor as their target.
Previously, antibody-based therapies have targeted the brain, with some showing promise in reaching the brain in humans.
Through the team’s screening technique, they identified an AAV named BI-hTFR1 that binds to the human transferrin receptor, enters human brain cells, and bypasses a human cell model of the blood-brain barrier.
Qin Huang, a co-first author on the study and a senior research scientist in Deverman’s lab, commented, “We have gained valuable insights from in vivo screens, but it has been challenging to find AAVs that work effectively across species.”fic protein targets. “Discovering one that can effectively interact with a human receptor is a significant advancement.”
The researchers utilized mice with a human equivalent of the transferrin receptor gene to test the AAVs in animal models. By injecting the AAVs into the bloodstream of these mice, they observed significantly higher levels of the AAVs in the brain and spinal cord compared to mice without the human transferrin receptor gene. This indicates that the receptor was actively transporting the AAVs across the blood-brain barrier.
The AAVs also demonstrateThe new AAVs have shown a significant increase in accumulation in brain tissue compared to AAV9, which is currently used in FDA-approved therapy for spinal muscular atrophy in infants but is not very effective in delivering cargo to the adult brain. The new AAVs were able to reach up to 71 percent of neurons and 92 percent of astrocytes in various areas of the brain.
In a study led by research scientist Jason Wu, Deverman’s team also utilized the AAVs to introduce 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 distributed throughout the brain.
The team stated that the new AAVs are well-suited for gene therapy because they target a human protein and have similar production and purification yields as AAV9 using scalable manufacturing methods. Apertura Gene Therapy, a biotech company co-founded by Deverman, is already working on developing new therapies using the AAVs to target the central nervous system.
With further development, the researchers believe it is possible to enhance the gene-delivery efficiency of their AAVs to the central nervous system, reduce their accumulation in the liver, and prevent inactivation by antibodies in some patients.
Sonia Vallabh and Eric Minikel, two researchers, are also involved in this project.The researchers at the Broad Institute who are working on treatments for prion disease are enthusiastic about the potential of AAVs to deliver brain therapies for humans.
“Gene therapy for a complex brain disease like prion disease requires widespread delivery and distribution in order to be effective,” explained Minikel. “Naturally occurring AAVs are not sufficient for this purpose. This custom-engineered capsid opens up a range of possibilities.”
