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Gene therapy can treat, and may even cure, certain genetic diseases, but getting therapeutic drugs to the parts of the body that need them is a challenge
.
Researchers have designed viruses called adeno-associated viruses (AAVs) to transport cargo — such as normal copies of genes — to specific cells and organs, but they don't always reach their intended destinations
.
Researchers at MIT and Harvard's Broad Institute have now developed a series of AAVs capable of reaching a particularly challenging target tissue — the brain
.
A study published in the journal Med by the team showed that their AAV is more than three times better at delivering cargo into primate brains than
AAV9, the current leading AAV delivery vehicle.
The new AAV is able to cross the blood-brain barrier, which prevents many drugs from entering the brain
.
They also accumulate much less in the liver than AAV9, which may reduce the risk of
liver side effects seen in other AAV9-based gene therapies.
This AAV family, known as the PAL family, may be a safer and more efficient way to deliver gene therapy to the brain
.
The AAV was designed in the lab of Pardis Sabeti, a member of the Broad School, a professor at Harvard University and the Harvard T.
H.
Chan School of Public Health, and a researcher
at the Howard Hughes Medical Institute.
"We generated a large number of randomly generated AAV capsids and shrunk them down to capsids capable of entering the brains of mice and macaques, delivering genetic cargo, and transcribing them into messenger RNA," said
Allie Stanton, lead author of the study and a graduate student in the Sabeti lab at Harvard Medical School.
Gene therapy consists of DNA, RNA, or other molecules that are transported
throughout the body through carriers or carriers.
AAVs are promising vectors because, as viruses, they efficiently transport their contents into
cells.
The scientists replaced the natural load of AAV with therapeutic DNA, gene-editing machinery, or other genetic information
they wanted to get into cells to treat disease.
"AAV is a very good gene therapy vector because you can put whatever you want into its shell, which will protect it and get it into a wide variety of cell types
," Stanton said.
However, most of the AAV doses injected usually end up in the liver, meaning that even a small fraction of AAV requires high doses of AAV to reach target tissues, such as the brain
.
In some cases, this has led to liver damage and even death
in clinical trials.
Engineered vectors that effectively 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 altering the amino acid composition of the viral shell, or capsid.
Because there are billions of AAV capsids that could be synthesized, scientists can modify thousands to millions of viruses at once to find viruses suitable for a specific purpose, such as crossing the blood-brain barrier
.
To develop a delivery system that could one day be used to treat difficult-to-treat neurological disorders, Stanton and his colleagues focused on inhibiting AAV
that crosses the blood-brain barrier.
They turned to a method developed by Sabeti's lab called DELIVER, in which scientists generate millions of capsids and look for AAVs
that can successfully deliver their loads to specific target cells.
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 generating therapeutic mRNA in macaque brains than AAV9
.
The team also found that the modified virus has a unique attraction
to the brain.
The liver of macaques treated with PAL contained only a quarter of the viral material in primates treated with AAV9, suggesting that the new capsids could help limit the liver toxicity
of other gene therapies.
Given the similarity between macaques and humans, PAL AAV may work in humans, the authors said, but added that AAV did not work in mice, making it difficult
to test these vectors in mouse disease models.
As a next step, the team hopes their work will provide a starting point
for more effective viral vectors.
"We are encouraged by the early results of the PAL series AAVS, and we can see several promising research directions using directed evolution and engineering techniques to further improve their efficiency
," Sabeti said.
Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression in the macaque CNS
