When the genome-editing tool CRISPR is thought of as a potential medicine, the targets that first come to mind are diseases like sickle cell or other conditions caused by particular mutations. Use CRISPR to fix that mutation, the idea goes, and you can treat the disease.
But a pair of abstracts being presented Sunday at a medical conference highlight how, just a decade after CRISPR’s debut, researchers are deploying the tool at diseases with more complicated roots that go beyond genetics. In this case, Alzheimer’s.
The research unveiled at the Alzheimer’s Association International Conference in Amsterdam is in its infancy, with results reported just from mice and lab-made mini-brains called organoids. But the projects, which rely on different strategies, underscore how scientists are trying to broaden their attacks on Alzheimer’s, a disease that has remained stubbornly difficult to crack.
“CRISPR is just another possible technology,” Maria Carrillo, the chief science officer of the Alzheimer’s Association, told STAT. “There’s always going to be a need for a variety of approaches.”
Carrillo pointed to a recent paper describing a Phase 1 trial of a different kind of genetic tool called an antisense oligonucleotide, or ASO, in Alzheimer’s as an example of how researchers are leveraging emerging technologies. Other teams have also been exploring using CRISPR to treat Alzheimer’s and neurodegenerative conditions.
“We’re just scratching the surface of that, but this is where we were 15 years ago with anti-amyloid approaches,” Carrillo said, referring to the types of medicines that are finally starting to show clinical benefits in patients.
In one project reported Sunday, a team from the University of California, San Diego, homed in not on that beta-amyloid protein itself, but on the gene that encodes its parent protein, called, perhaps unsurprisingly, amyloid precursor protein, or APP.
There are different pathways that emerge out of APP, some of which are actually protective, but some of which result in the formation of beta-amyloid, which is thought to contribute to Alzheimer’s. In people with Alzheimer’s disease, the APP scale gets tipped toward the amyloid end.
With their approach, the researchers sought to tilt the scale back toward the healthier end. They used CRISPR to snip out a small amount from the end of the APP gene in mice bred to have a version of Alzheimer’s, finding that the method worked to reduce the amount of amyloid produced.
“Classically, people are thinking of CRISPR as mutation correction,” said postdoc Brent Aulston, who led the work. “Ours is much different than that.”
The research team now has a grant to refine the technology in hopes of one day testing it in people, a process that will likely take years. They plan to explore which CRISPR enzyme and piece of guide RNA — the components of the technology that deliver CRISPR to the right spot in the genome and cut the gene — work best, and how to come up with a version that could be deployed in human brain cells.
“That’s the next step,” said Subhojit Roy, a professor at UCSD and a senior researcher on the effort.
The other project described Sunday focused on a type of Alzheimer’s in which the versions of a gene a person inherits do play a major role. A gene called APOE has different forms, and one known as APOE4 raises the risk of developing Alzheimer’s, particularly when someone has two copies.
For their work, scientists at Duke University aimed to use CRISPR to tamp down the activity of APOE4. To do so, they sicced their CRISPR complex not at APOE, but rather at the epigenome, the halo of chemicals around DNA that regulates the activity of genes. Hitting the right spot on the epigenome essentially closed off the APOE4 gene, limiting its expression in mice, the researchers reported. Notably, the CRISPR complex they designed only affected the activity of APOE4, leaving the healthy versions untouched.
“The concept is to reduce the production of this pathogenic variant of APOE,” said Ornit Chiba-Falek, the chief of translational brain sciences at Duke University Medical Center and one of the researchers involved.
Chiba-Falek and her Duke colleague Boris Kantor have started a company called CLAIRIgene to advance their epigenome-targeted approaches for Alzheimer’s and other neurodegenerative diseases. She said given the complexity of diseases like Alzheimer’s, different approaches may ultimately need to be combined to treat it.
“There is no magic bullet for this disease,” Chiba-Falek said.