Publications by authors named "P Perez-Pinera"
Exon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which have broad applications in medicine and biotechnology. Existing techniques including antisense oligonucleotides, targetable nucleases, and base editors, while effective for specific applications, remain hindered by transient effects, genotoxicity, and inconsistent exon skipping. To overcome these limitations, here we develop SPLICER, a toolbox of next-generation base editors containing near-PAMless Cas9 nickase variants fused to adenosine or cytosine deaminases for the simultaneous editing of splice acceptor (SA) and splice donor (SD) sequences.
View Article and Find Full Text PDFHypoxia-induced alternative splicing (AS) regulates tumor progression and metastasis. Little is known about how such AS is controlled and whether higher-order genome and nuclear domain (ND) organizations dictate these processes. We observe that hypoxia-responsive alternatively spliced genes position near nuclear speckle (NS), the ND that enhances splicing efficiency.
View Article and Find Full Text PDFHuntington's disease (HD) is an inherited and ultimately fatal neurodegenerative disorder caused by an expanded polyglutamine-encoding CAG repeat within exon 1 of the huntingtin (HTT) gene, which produces a mutant protein that destroys striatal and cortical neurons. Importantly, a critical event in the pathogenesis of HD is the proteolytic cleavage of the mutant HTT protein by caspase-6, which generates fragments of the N-terminal domain of the protein that form highly toxic aggregates. Given the role that proteolysis of the mutant HTT protein plays in HD, strategies for preventing this process hold potential for treating the disorder.
View Article and Find Full Text PDFArticle Synopsis
- Exon skipping technologies allow for the removal of specific exons from mRNA, benefiting various fields like molecular biology and medicine, but existing methods face challenges such as temporary effects or potential harm to cells.
- The newly developed SPLICER toolbox uses advanced base editing techniques to simultaneously modify specific splice sites, improving the reliability of exon skipping and minimizing unwanted mutations.
- In tests, SPLICER effectively targeted exon 17 linked to Alzheimer's disease, leading to reduced toxic peptide formation and promising results for potential treatments.