A team of US researchers has developed an innovative gene editing tool called SPLICERwhich manages to reduce the formation of amyloid-beta plaque precursors, a characteristic feature of Alzheimer’s disease, in mouse models. This preview, published in the magazine ‘Nature Communications‘, promises new possibilities for the treatment of genetic and neurodegenerative diseases.
Led by Professor Pablo Pérez-Pinera, from the University of Illinois at Urbana-Champaignthe team applied SPLICER to skip specific regions of genes that contain problematic mutations, using an approach known as exon skipping. This method allows cells to avoid defective sections of DNA that produce toxic or misfolded proteins, as occurs in diseases such as Duchenne muscular dystrophy or Huntington’s disease.
«Imagine DNA as a recipe book -explains Pérez-Pinera-. If a page has an error that makes the recipe inedible, SPLICER allows you to skip that page and continue with the rest of the book, obtaining a functional, although not perfect, result.
SPLICER uses an advanced version of the CRISPR-Cas9 gene editing platform, with significant improvements. While traditional CRISPR-Cas9 requires specific DNA sequences to work, SPLICER uses new Cas9 enzymes that remove that restriction, allowing it to act on genes that were previously inaccessible, such as those related to Alzheimer’s disease.
Additionally, SPLICER addresses the precision of the exon skipping process. “With current methods, a part of the unwanted exon often remains, which can generate defective proteins,” he details. Angelo Miskalisgraduate student and co-lead author of the study. SPLICER edits both the start and end sequences of exons, achieving more complete and precise skipping.
In the study, the researchers applied SPLICER to a gene associated with the formation of amyloid-beta plaques, which accumulate in brain neurons as Alzheimer’s progresses. In neuron cultures, SPLICER was able to efficiently reduce the production of these plaques.
Success in mice
In mice treated with SPLICER, genetic analysis revealed a 25% decrease in the target exon of brain DNA and RNA, without unwanted side effects. “This advance shows that we can achieve more efficient exon skipping than with previous methods,” says Shraddha Shirguppe, another co-lead author of the work.
Although promising, the exon skipping strategy has limitations, as it only works if the resulting protein maintains essential functions. “For diseases such as Alzheimer’s, Parkinson’s, Huntington’s or Duchenne, this technique could be revolutionary,” said Pérez-Pinera.
Next steps include evaluating the long-term safety of this gene editing in animal models and analyzing its impact on the progression of neurodegenerative diseases.
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