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BNA Gapmers revert splicing and reduce RNA foci

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09/15/2017

BNA Gapmers revert splicing and reduce RNA foci

BNANC gapmers revert splicing defects in myotonic dystrophy type 1 (DM1) cells. DM1 is a multisystemic disease caused by an expanded CTG repeat in the 3’-untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Gapmers targeting within the repetitive region of DMPK preferentially degrades the mutant allele. 



Myotonic dystrophy is the most common type of muscular dystrophy. In DM1 the expanded CUG repeat RNA (CUGexp RNA) is retained in the nucleus where it forms RNA foci which lead to defects in regulated alternative splicing events during development. Therefore if the development of CUG expanded repeat RNA foci could be prevented, the disorder will not materialize.

To test this, Manning et al. used the antisense BNA gapmer strategy to degrade CUG expanded repeat (CUGexp) RNA in immortalized human TeloMyoD fibroblast cell lines expressing telomerase and containing a tetracycline-inducible MyoD to promote the myogenic program in response to growth. A FISH probe targeting the repeat RNA was used for visualization of the RNA foci in the untreated and treated cells.

BNANC gapmers targeting within the repetitive region of DMPK preferentially degrade the mutant allele thereby decreasing RNA foci. Manning et al. were able to show that antisense BNANC gapmers could be used to potentially revert splicing defects in myotonic dystrophy type 1 (DM1) cells.

RNA foci are a result of expanding RNA repeats that are retained in the nucleus, and adopt unusual secondary structures, sequester various RNA binding proteins, and can become toxic to the cell. RNA-RNA binding protein complexes or aggregates form insoluble nuclear foci causing cellular defects. The abnormal expansion of nucleotide repeats leads to numerous effects on genes such as the inhibition of transcription and the loss-of-function of proteins, leading to the disease.


Reference
Kassie S. Manning, Ashish N. Rao, Miguel Castro, and Thomas A. Cooper; BNANC Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells. ACS Chem. Biol., Article ASAP. DOI: 10.1021/acschembio.7b00416. 

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