New gene editing treatment extends lifespan of prion disease mice

Researchers at the Massachusetts Institute of Technology's Broad Institute and Harvard University have developed a gene-editing treatment for prion disease that extends the lifespan of a mouse model of the deadly neurodegenerative condition by about 50 percent. The treatment, which uses base editing to change single letters in DNA, reduced levels of the disease-causing prion protein in the brain by 60 percent.

There is currently no cure for prion disease, and this new approach could be an important step toward treatments that can prevent prion disease or slow its progression in patients who have already developed symptoms. Base editing approaches also have the potential to be a one-time treatment for all prion disease patients, regardless of symptoms. genetic mutation causing their illness.

The study, led by Broad senior group leaders Sonia Vallabh and Eric Minikel and Broad Core Institute member David Liu, found that lowering levels of the prion protein in animals infected with human-type prions It was demonstrated for the first time that the life span of protein. Here are the findings: natural medicine.

As patient scientists, I often think about how lucky we are to be tackling this problem right now. When I received my genetic test report in 2011, base editing was still unknown to the world. We are deeply honored to have the opportunity to direct these powerful new tools against our diseases. ”

Sonia Vallabh, Senior Group Leader, Broad Institute, MIT and Harvard University

“It was incredible to combine our disease models with this gene editing technology,” Minikel said.

“Our laboratory is grateful to Eric, who brings tremendous expertise, scientific rigor, and dedication to this collaboration,” said Liu, the Richard Merkin Professor and director of the Merkin Institute for Transformative Technology. I am very fortunate to have had the opportunity to collaborate with Sonia.” in a wide range of healthcare fields. “We hope that these results will aid in the future development of one-off treatments for this important class of diseases.”

Meirui An and Jessie Davis were graduate students in Liu's lab at the time of the project and are co-lead authors on the study.

“Prion diseases have many different causes; some are genetic, some are naturally occurring, some are caused by infection, and we believe this base editing strategy can be applied to all these forms of prion diseases.” ” said Mr. Anne. “This has the potential to be a very promising strategy.”

long-awaited strategy

Mr. Vallabh and Mr. Minikel have been suffering from prion disease since 2012, after Mr. Vallabh's mother died from a disease called Fatal Familial Insomnia and learned that Mr. Vallabh had inherited the disease-causing mutation. Conducting research. A wife and husband team started a laboratory in the Broad with a singular focus: the lifelong prevention and treatment of prion diseases.

Shortly after CRISPR-Cas9 gene editing was developed in 2013, Vallabh and Minikel began wondering if CRISPR could be used to disrupt the gene that encodes the prion protein. Minikel remembers thinking, “There's some real promise there. We could do something with this.”

In 2018, Liu, who works on the same floor as Minikel and Vallabh at Broad, approached them and suggested a collaboration. His lab had just developed base editing, a gene-editing approach that can stop protein production using strategies such as changing a single letter of DNA and incorporating a “stop” signal into the genetic code.

By studying population databases such as the Genome Aggregation Database (gnomAD), Vallabh and Minikel show that R37X, a naturally occurring mutation in the prion gene, reduces protein levels in humans without causing harmful side effects. I knew that. This gave hope that using base editing to introduce the same mutations might be able to prevent the disease.

“We realized there was a great opportunity to use human genetics to inform base editing,” Minikel said.

brain delivery

In the new study, the team showed that the base editor installed R37X editing efficiently and with few unwanted side products in human cells. But the researchers needed to deliver the basic editor to the brain.

Building on previous work by Ben Deberman's vector engineering lab at Broad University, the team developed a pair of adeno-associated viruses (AAVs) to package and deliver base editing machinery to brain cells. . They then administered AAV to mice infected with human prion protein.

On average, this system introduced R37X editing in 37% of the copies of the gene and reduced prion protein levels by 50% compared to mice that did not receive treatment. The lifespan of the mouse was also increased by about 50 percent.

The scientists made a series of improvements to the system to increase editing efficiency and limit distribution to other organizations. With their improved system, they observed a 63 percent reduction in prion protein levels at one-sixth the dose of AAV.

Dual AAVs are expensive to manufacture, so the team wants to make the base editing cargo smaller in the future. They also used prime editing, which can introduce more complex DNA edits than single base changes, to introduce protective mutations that ensure that the prion protein itself is benign, rather than halting protein production. They also plan to develop strategies for use.

“We still have a long way to go to establish this as a treatment,” Minikel said. “But it's really exciting to see how much potential there is.”