A new gene editing approach that helps cells skip problematic gene regions successfully reduced amyloid-beta plaque precursors in mice, marking a potential advance in Alzheimer’s disease treatment research.
Published in Nature Communications | Estimated reading time: 4 minutes
Researchers at the University of Illinois Urbana-Champaign have developed an innovative gene editing tool called SPLICER that allows cellular machinery to bypass portions of genes responsible for disease-causing proteins. In their first therapeutic demonstration, they successfully applied it to reduce proteins associated with Alzheimer’s disease plaque formation.
“DNA contains the instructions to build everything that is responsible for how cells function. So it’s like a book of recipes that contains very detailed instructions for cooking,” said Pablo Perez-Pinera, professor of bioengineering at the U. of I. “But there are large regions of DNA that don’t code for anything. It’s like, you start the recipe for a turkey dinner, and then you hit a note that says, ‘continued on page 10.’ After page 10, it’s ‘continued on page 25.’ The pages between are gibberish.”
The technology builds upon the widely-used CRISPR-Cas9 gene editing system but makes key improvements. While traditional CRISPR requires specific DNA sequences to function, SPLICER uses newer enzymes that can work on a broader range of genetic targets. This flexibility allowed the team to successfully target genes involved in Alzheimer’s disease that were previously unreachable.
“Another problem we address in our work is precision in what gets skipped,” said graduate student Angelo Miskalis, a co-first author of the paper. “With current exon-skipping techniques, sometimes not all of the exon gets skipped, so there’s still part of the sequence we don’t want expressed. In the cookbook analogy, it’s like trying to skip a page, but the new page starts in the middle of a sentence, and now the recipe doesn’t make sense. We wanted to prevent that.”
The researchers demonstrated SPLICER’s effectiveness by targeting a gene involved in forming amyloid-beta, the protein that accumulates into plaques in Alzheimer’s disease. When analyzed in cultured neurons, SPLICER efficiently reduced amyloid-beta formation. In live mice, the targeted gene region was decreased by 25%, with no evidence of off-target effects in other genes.
“Exon skipping only works if the resulting protein is still functional, so it can’t treat every disease with a genetic basis. That’s the overall limitation of the approach,” Perez-Pinera explained. “But for diseases like Alzheimer’s, Parkinson’s, Huntington’s or Duchenne’s muscular dystrophy, this approach holds a lot of potential.”
Glossary:
- SPLICER: A gene editing tool that helps cells skip over problematic portions of genes while reading genetic instructions
- Exon: A segment of a gene that contains instructions for making proteins
- Amyloid-beta: A protein that accumulates to form plaques in the brains of Alzheimer’s disease patients
Test Your Knowledge
What advantage does SPLICER have over traditional CRISPR-Cas9?
SPLICER can work on a broader range of genetic targets because it doesn’t require specific DNA sequences to function.
How much did SPLICER reduce the targeted gene region in mice?
The targeted gene region was decreased by 25% with no evidence of off-target effects.
What is the key limitation of exon skipping as a treatment approach?
Exon skipping only works if the resulting protein remains functional after the targeted section is removed, so it can’t treat every genetic disease.
How does SPLICER’s approach to precision differ from current exon-skipping techniques?
SPLICER ensures complete skipping of targeted gene regions, whereas current techniques sometimes result in partial skipping that can leave problematic sequences expressed.
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