Antisense-mediated Exon Skipping Decreases Tau Protein Expression: A Potential Therapy For Tauopathies.

TitleAntisense-mediated Exon Skipping Decreases Tau Protein Expression: A Potential Therapy For Tauopathies.
Publication TypeJournal Article
Year of Publication2014
AuthorsSud R, Geller ET, Schellenberg GD
JournalMol Ther Nucleic Acids
Volume3
Paginatione180
Date Published2014 Jul 29
ISSN2162-2531
Abstract

In Alzheimer's disease, progressive supranuclear palsy, and a number of other neurodegenerative diseases, the microtubule associated protein tau aggregates to form intracellular neurofibrillary tangles and glial tangles, abnormal structures that are part of disease pathogenesis. Disorders with aggregated tau are called tauopathies. Presently, there are no disease-modifying treatments for this disease class. Tau is encoded by the MAPT gene. We propose that reducing MAPT expression and thus the amount of tau protein made could prevent aggregation, and potentially be an approach to treat tauopathies. We tested 31 morpholinos, complementary to the sense strand of the MAPT gene to identify oligonucleotides that can downregulate MAPT expression and reduce the amount of tau protein produced. Oligonucleotides were tested in human neuroblastoma cell lines SH-SY5Y and IMR32. We identified several morpholinos that reduced MAPT mRNA expression up to 50% and tau protein levels up to ~80%. The two most potent oligonucleotides spanned the 3' boundary of exons 1 and 5, masking the 5'-splice sites of these exons. Both morpholinos induced skipping of the targeted exons. These in vitro findings were confirmed in mice transgenic for the entire human MAPT gene and that express human tau protein. These studies demonstrate the feasibility of using modified oligonucleotides to alter tau expression.

DOI10.1038/mtna.2014.30
Alternate JournalMol Ther Nucleic Acids
PubMed ID25072694
PubMed Central IDPMC4121519
Grant ListR37 AG011762 / AG / NIA NIH HHS / United States