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Gene-delivering viruses reach the brain in a step toward gene therapy for neurological diseases

Gene-delivering viruses reach the brain in a step toward gene therapy for neurological diseases

Gene-delivering viruses reach the brain in a step toward gene therapy for neurological diseases

Summary: Researchers have developed a family of adeno-associated virus (AAV) vectors that are able to cross the blood-brain barrier and deliver gene therapies directly into the brain.

Source: Broad Institute

Gene therapies can treat, even potentially cure, certain genetic diseases, but the challenge is to deliver the treatments to the parts of the body where they are needed.

Researchers have engineered viruses called adeno-associated viruses (AAVs) to deliver cargo—such as a functional copy of a gene—to specific cells and organs, but they don’t always reach their intended destination.

Researchers at the Broad Institute of MIT and Harvard have now developed a family of AAVs that are able to reach a particularly challenging target tissue – the brain. The team shows, in a study published in Withthat their AAVs are more than three times better at delivering their cargo into the primate brain than the current leading delivery AAV, AAV9.

The new AAVs can cross the blood-brain barrier, which prevents many drugs from reaching the brain. They also accumulate much less in the liver than AAV9, potentially reducing the risk of liver side effects seen with other AAV9-based gene therapies. This family of AAVs, called the PAL family, could be a safer and more effective way to deliver gene therapies to the brain.

The AAVs were designed in the laboratory of Pardis Sabeti, who is an institute member at the Broad, a professor at Harvard University and the Harvard TH Chan School of Public Health, and a researcher at the Howard Hughes Medical Institute.

“We generated a huge pool of randomly generated AAV capsids and narrowed it down from there to those that can get into the brains of both mice and macaques, deliver genetic cargo and actually transcribe it into mRNA,” said lead study author Allie Stanton, a Harvard Medical School graduate student in the lab. Sabeti.

Protective shell

Gene therapies consist of DNA, RNA or other molecules that are carried around the body by means of transport or vectors. AAVs are promising vectors because, like viruses, they are efficient in delivering their contents into cells. Scientists replace the AAV’s natural cargo with therapeutic DNA, gene-editing machines, or other genetic information they want to introduce into cells to treat disease.

“AAVs are a really good gene therapy vector because you can put whatever you want in its shell, which will protect it and get it into a wide variety of cell types,” Stanton said.

However, most of the injected dose of AAV usually ends up in the liver, meaning that high doses of AAV are needed to get even a fraction into a different target tissue, such as the brain. In some cases, these high doses have led to liver damage and even death in clinical trials.

Gene therapies consist of DNA, RNA or other molecules that are carried around the body by means of transport or vectors. Image is in the public domain

Engineering vectors to efficiently target specific cells or organs can help reduce these unwanted side effects. Gene therapy researchers are working to make AAV safer and more effective by changing the amino acid composition of the virus’s shell, or capsid.

Because there are billions of possible synthetic AAV capsids, scientists can modify thousands to millions of viruses at a time to search for ones that fit a particular purpose — such as crossing the blood-brain barrier.

Building better vectors

To develop a delivery system that could one day be used for hard-to-treat neurological diseases, Stanton and colleagues focused on identifying AAVs that cross the blood-brain barrier.

They turned to a method developed in the Sabeti lab called DELIVER, in which scientists create millions of capsids and search for AAVs that successfully deliver their cargo to specific target cells.

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Gene-delivering viruses reach the brain in a step toward gene therapy for neurological diseases

Using DELIVER, the team developed the PAL family of AAVs that cross the blood-brain barrier more efficiently than AAV9 — the only viral vector approved by the FDA for use in the nervous system.

They found that PAL AAVs were three times more efficient at producing therapeutic mRNA in the macaque brain compared to AAV9.

The team also found that engineered viruses have a unique attraction to the brain. PAL-treated macaques had one-fourth the viral material in their livers as AAV9-treated primates, suggesting that the new capsids could help limit the liver toxicity of other gene therapies.

The authors say that PAL AAVs could potentially work in humans given how similar macaques are to humans, but add that the AAVs did not work well in mice, making it difficult to test these vectors in mouse models of the disease. Going forward, the team hopes their work will provide a starting point for even more efficient viral vectors.

“We are encouraged by the early results of the PAL family of AAVS and can see several promising lines of research using directed evolution and engineering to further increase their efficiency,” said Sabeti.

financing: This research was supported in part by an anonymous philanthropic gift, the Howard Hughes Medical Institute, the National Institutes of Health, a Shark Tank Award from the Chemical Biology and Therapeutic Sciences Program at the Broad Institute, and the American Gene and Genomics Society. Cell Therapy.

About this news about gene therapy research

Author: Karen Zusi
Source: Broad Institute
Contact: Karen Zusi – Broad Institute
picture: Image is in the public domain

Original Research: Findings will appear in WITH



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