Gene therapies can treat, even potentially cure, certain genetic diseases, but it surely is difficult to deliver the treatments to the parts of the body where they’re needed. Researchers have engineered viruses called adeno-associated viruses (AAVs) to deliver cargo -; comparable to a functioning copy of a gene -; to specific cells and organs, but they do not all the time get to their desired destination.
Researchers on the Broad Institute of MIT and Harvard have now developed a family of AAVs that’s capable of reach a very difficult goal tissue -; the brain. The team shows, in a study published in Med, that their AAVs are greater than thrice higher at delivering their cargo into the primate brain than the present leading AAV delivery vehicle, AAV9.
The brand new AAVs can cross the blood-brain barrier, which keeps many drugs from moving into the brain. In addition they accumulate much less within the liver than AAV9, potentially reducing the chance of liver unwanted side effects which were seen in other AAV9-based gene therapies. This family of AAVs, called the PAL family, may very well be a safer and more efficient technique to deliver gene therapies to the brain.
The AAVs were designed within the lab of Pardis Sabeti, who’s an institute member on the Broad, a professor at Harvard University and the Harvard T.H. Chan School of Public Health, and a Howard Hughes Medical Institute investigator.
We generated an enormous pool of randomly generated AAV capsids and from there narrowed right down to ones capable of get into the brain of each mice and macaques, deliver genetic cargo, and truly transcribe it into mRNA.”
Allie Stanton, study lead writer, a Harvard Medical School graduate student within the Sabeti lab
A protective shell
Gene therapies consist of DNA, RNA, or other molecules which are transported across the body by delivery vehicles, or vectors. AAVs are promising vectors because as viruses, they’re effective at delivering their contents into cells. Scientists replace the AAVs’ natural payloads with therapeutic DNA, gene-editing machinery, or other genetic information that they wish to get inside cells to treat disease.
“AAVs are a extremely good gene therapy vector because you’ll be able to put whatever you wish within its shell, which is able to protect it and get it right into a wide range of cell types,” said Stanton.
Nevertheless, the vast majority of an injected AAV dose typically results in the liver, meaning that top doses of AAV are required to get even a fraction into a special goal tissue, comparable to the brain. In some cases, these high doses have resulted in liver damage and even death in clinical trials.
Engineering vectors to efficiently goal specific cells or organs could help reduce these unwanted unwanted side effects. Gene therapy researchers are working to make AAVs safer and simpler by changing the amino acid makeup of the virus’ shell, or capsid. Because there are billions of possible synthetic AAV capsids, scientists can modify 1000’s to tens of millions of viruses at a time to look for ones that fit a selected purpose -; comparable to crossing the blood-brain barrier.
Constructing higher vectors
To develop a delivery system that may at some point be used for hard-to-treat neurological diseases, Stanton and colleagues focused on pinning down AAVs that cross the blood-brain barrier. They turned to a technique developed within the Sabeti lab called DELIVER, through which scientists generate tens of millions of capsids and search for AAVs that successfully deliver their payload to certain goal cells. Using DELIVER, the team developed the PAL family of AAVs that cross the blood-brain barrier more effectively than AAV9 -; the one FDA-approved viral vector to be used within the nervous system.
They found that the PAL AAVs were thrice simpler at producing therapeutic mRNA within the macaque brain in comparison with AAV9.
The team also found that the engineered viruses had a novel pull to the brain. PAL-treated macaques had one-fourth of the viral material of their livers as AAV9-treated primates did, suggesting that the brand new capsids could help limit the liver toxicity of other gene therapies.
The authors say PAL AAVs could potentially work in humans given how similar macaques are to humans, but added that the AAVs didn’t work well in mice, making it difficult to check these vectors in mouse models of disease. Moving forward, the team hopes that their work will provide a start line for even simpler viral vectors.
“We’re encouraged by the early results of the PAL family AAVS, and might see several promising lines of investigation using directed evolution and engineering to further increase their efficiency,” Sabeti said.
Source:
Broad Institute of MIT and Harvard
Journal reference:
Stanton, A.C., et al. (2022) Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression within the macaque CNS. Med. doi.org/10.1016/j.medj.2022.11.002.