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Alternative splicing in disease and therapy

Abstract

Alternative splicing is the major source of proteome diversity in humans and thus is highly relevant to disease and therapy. For example, recent work suggests that the long-sought-after target of the analgesic acetaminophen is a neural-specific, alternatively spliced isoform of cyclooxygenase 1 (COX-1). Several important diseases, such as cystic fibrosis, have been linked with mutations or variations in either cis-acting elements or trans-acting factors that lead to aberrant splicing and abnormal protein production. Correction of erroneous splicing is thus an important goal of molecular therapies. Recent experiments have used modified oligonucleotides to inhibit cryptic exons or to activate exons weakened by mutations, suggesting that these reagents could eventually lead to effective therapies.

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Figure 1: Cis-acting elements that control splicing.

Bob Crimi

Figure 2: Mutations in the MAPT gene that affect 4R/3R ratio.

Bob Crimi

Figure 3: Alternative splicing and therapy.

Bob Crimi

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Acknowledgements

The authors thank Ed Otto and Jean-Marc Gallo for critically reading the manuscript, and members of the Garcia-Blanco laboratory for helpful suggestions. The authors also thank Annette Kennett for help in preparing the manuscript and Candy Webster for expert work on the figures. M.A.G.-B. acknowledges support from National Institutes of Health grants RO1 GM63090 and R33 CA97502.

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Correspondence to Mariano A Garcia-Blanco.

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M.A.G.-B. is a founder of and consultant for Intronn, which owns and is commercializing methods described in this review.

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Garcia-Blanco, M., Baraniak, A. & Lasda, E. Alternative splicing in disease and therapy. Nat Biotechnol 22, 535–546 (2004). https://doi.org/10.1038/nbt964

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