Researchers at the Broad Institute of MIT and Harvard have developed a gene-editing treatment for prion disease that extends lifespan by about 50 percent in a mouse model of the fatal neurodegenerative condition. The treatment, which uses base editing to make a single-letter change in DNA, reduced levels of the disease-causing prion protein in the brain by as much as 60 percent.
There is currently no cure for prion disease, and the new approach could be an important step towards treatments that prevent the disease or slow its progression in patients who have already developed symptoms. A base-editing approach could also likely be a one-time treatment for all prion disease patients regardless of the genetic mutation causing their disease.
The work, led by Broad senior group leaders Sonia Vallabh and Eric Minikel , as well as Broad core institute member David Liu , is the first demonstration that lowering levels of the prion protein improves lifespan in animals that have been infected with a human version of the protein. The findings appear in Nature Medicine .
"As a patient scientist, I think often about how lucky we are to be coming at this problem now," said Vallabh. "When I received my genetic test report in 2011, the world had never heard of base editing. It's a huge privilege to have the opportunity to point these powerful new tools at our disease."
"It's been incredible to merge our disease models with this gene-editing technology," Minikel said.
"Our lab is very fortunate to have the opportunity to work with Eric and Sonia, who have brought tremendous expertise, scientific rigor, and total dedication to this collaboration," said Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad. "We are hopeful the results might inform the future development of a one-time treatment for this important class of diseases."
Meirui An and Jessie Davis, both graduate students in Liu's lab at the time of the project, are co-first authors on the study.
"Prion disease has a lot of different origins — some are genetic, some occur spontaneously, and others stem from infections — but we believe this base editing strategy can be applied to all of these forms of prion disease," An said. "This has the potential to be a really promising strategy."
A long-awaited strategy
Vallabh and Minikel have been studying prion disease since 2012, after Vallabh's mother passed away from a form of the disease called fatal familial insomnia and Vallabh found out that she had inherited the disease-causing mutation. The wife-and-husband team started a lab at the Broad with a singular focus: preventing and treating prion disease within their lifetime.
Not long after the development of CRISPR-Cas9 gene editing in 2013, Vallabh and Minikel began thinking about whether CRISPR could be used to disrupt the gene encoding the prion protein. Minikel remembers thinking, "There's something really promising there. We should be able to do something with this."
In 2018, Liu, who works on the same floor as Minikel and Vallabh at Broad, approached them and proposed a collaboration. His lab had just developed base editing, a gene-editing approach that makes single-letter changes in DNA and can shut down protein production using strategies including installing a "stop" signal in the genetic code.
Vallabh and Minikel knew from studying population databases such as the Genome Aggregation Database ( gnomAD ) that R37X, a naturally occurring mutation in the prion gene, reduced protein levels without harmful side effects in people. That gave them hope that installing the same mutation using base editing might be protective against the disease.
"We realized it was this golden opportunity to use human genetics to inform base editing," Minikel said.
Brain delivery
In the new study, the team showed that a base editor installed the R37X edit in human cells efficiently and with few unwanted byproducts. But the researchers needed to deliver the base editors to the brain.
Building on previous work by the vector-engineering lab of Ben Deverman at the Broad, the team developed a pair of adeno-associated viruses (AAVs) to package and deliver the base-editing machinery to brain cells. They then administered the AAVs to mice infected with the human prion protein.
On average, the system installed the R37X edit in 37 percent of copies of the gene, reducing levels of the prion protein by 50 percent compared to mice without the treatment. The mice also lived about 50 percent longer.
The scientists made a swath of improvements to their system to boost editing efficiency and limit delivery to other tissues. With their improved system, they observed 63 percent lower prion protein levels at a six-fold lower dose of AAVs.
In the future, the team hopes to make the base-editing cargo smaller, because dual AAVs can be costly to produce. They also plan to develop a strategy that uses prime editing — which can install more complicated DNA edits than single-base changes — to install a protective mutation that does not shut down protein production but rather ensures that the prion protein itself is benign.
"There's still a long way to go to make this a therapy," Minikel said. "But it's really exciting to see how much is possible."
