Researchers have developed a gene-editing treatment for prion disease that can nearly double the lifespan of mouse models suffering from this deadly neurodegenerative condition. This novel approach utilizes base editing to make tiny adjustments in DNA, effectively lowering the levels of harmful prion proteins in the brain by as much as 60%. The results suggest that decreasing the amount of prion protein can significantly improve the lifespan of animals infected with a human variant of this protein.
Scientists at the Broad Institute of MIT and Harvard have devised a gene-editing treatment targeting prion disease that can increase lifespan by nearly 50% in mouse models of this severe neurodegenerative disorder. This groundbreaking treatment employs base editing to modify DNA slightly, achieving a notable decrease in harmful prion protein levels in the brain of up to 60%.
At present, there is no known cure for prion disease, making this new approach a potentially crucial breakthrough towards developing treatments that could either prevent the onset of the disease or slow its advancement in patients who have already displayed symptoms. The base-editing technique may serve as a one-time therapy for all individuals affected by prion diseases, regardless of the specific genetic mutation causing their illness.
This study, spearheaded by senior group leaders Sonia Vallabh and Eric Minikel from Broad, alongside David Liu, a core member of the institute, is the first to demonstrate that reducing prion protein levels can improve the lifespan of animals exposed to a human variant of the protein. Their findings were published in Nature Medicine.
“As a patient scientist, I often consider how fortunate we are to address this issue now,” Vallabh expressed. “When I learned my genetic test results in 2011, the concept of base editing was entirely new. It’s a tremendous privilege to utilize these powerful new tools for our disease.”
“Combining our disease models with this gene-editing technology has been nothing short of incredible,” added Minikel.
“Our lab is extremely fortunate to collaborate with Eric and Sonia, whose vast expertise, scientific rigor, and unwavering dedication have been invaluable to this project,” mentioned Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at Broad. “We are hopeful that the results could guide the future creation of a one-time treatment for this essential category of diseases.”
Co-first authors of this study include Meirui An and Jessie Davis, both graduate students who contributed to the project in Liu’s lab.
“Prion disease can result from various causes — some inheritably, others spontaneously, and some through infections — and we believe that this base editing technique could be applied to all forms of prion diseases,” An commented. “This could be a promising pathway for treatment.”
A long-anticipated approach
Since 2012, Vallabh and Minikel have been focused on prion disease research, driven partly by Vallabh’s personal experience: her mother passed away from fatal familial insomnia, a variant of the disease, and Vallabh discovered she inherited the mutation associated with it. The couple established a lab at the Broad with a clear goal: to prevent and treat prion diseases in their lifetime.
After the introduction of CRISPR-Cas9 gene editing technology in 2013, Vallabh and Minikel began to consider the feasibility of using CRISPR to disrupt the gene responsible for producing the prion protein. Minikel recalls thinking, “This has real potential. We should be able to utilize this technology.”
In 2018, Liu, who shares a floor with Minikel and Vallabh at Broad, proposed a collaboration after his lab had developed base editing, a precise technique allowing single-letter changes in DNA and capable of halting protein synthesis by adding a “stop” signal in the genetic code.
Vallabh and Minikel already knew from surveys of population databases like the Genome Aggregation Database (gnomAD) that a mutation called R37X, found in the prion gene, can lower prion protein levels in humans without any harmful effects. This finding inspired them to pursue the replication of this mutation via base editing to potentially protect against the disease.
“We saw this as a golden opportunity to apply human genetics to inform base editing,” Minikel elaborated.
Delivery to the brain
In their recent study, the researchers illustrated that a base editor could efficiently introduce the R37X mutation into human cells with minimal unwanted side effects. One significant challenge, however, was delivering the base editors to the brain.
Leveraging previous work from Ben Deverman’s vector-engineering lab at Broad, they produced two adeno-associated viruses (AAVs) designed to transport the base-editing tools directly to brain cells, which they subsequently administered to mice infected with human prion protein.
Their system successfully introduced the R37X mutation into, on average, 37% of gene copies, achieving a 50% reduction in prion protein levels compared to untreated mice. The treated mice also showed an approximate 50% increase in lifespan.
The team made numerous improvements to their delivery system to boost editing efficiency while limiting impacts on other tissues. As a result, they achieved a 63% reduction in prion protein levels while using six times less AAVs.
Looking ahead, the team hopes to refine the size of the base-editing components, as producing dual AAVs can be costly. They also plan to investigate the potential of prime editing, which allows for more complex DNA modifications beyond just single-base alterations, to insert a protective mutation that maintains the prion protein’s functionality but renders it harmless.
“There is still a considerable amount of work ahead before this can become an effective therapy,” Minikel recognized. “Nonetheless, it’s truly exciting to witness the strides being made.”
This research received partial funding from the National Institutes of Health, Prion Alliance, and the Howard Hughes Medical Institute.
