Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.4 (RNase H)
 2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease caused by abnormal transcripts containing expanded CUG repeats. The CUG transcripts aggregate in the nucleus to form RNA foci and lead to nuclear depletion of Muscleblind-like 1 (MBNL1) and stabilized expression of CUGBP Elav like family 1 (CELF1), both of which are splicing regulatory proteins. The imbalance of these proteins results in misregulation of alternative splicing and neuromuscular abnormalities. Here, we report the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in DM1. We designed chimeric ASOs, termed gapmers, containing modified nucleic acid residues to induce RNase H-mediated degradation of CUG-repeat transcripts. The gapmers selectively knockdown expanded CUG transcripts and are sufficient to disrupt RNA foci both in cell culture and mouse models for DM1. Furthermore, combination of gapmers with morpholino ASOs that help release binding of MBNL1 to the toxic RNA can potentially enhance the knockdown effect. Additional optimization will be required for systemic delivery; however, our study provides an alternative strategy for the use of ASOs in DM1 therapy.
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PMID:RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. 2237 89

Myotonic dystrophy (DM) types 1 (DM1) and 2 (DM2) are caused by autosomal dominant gain-of-function RNA which are, in turn, created by the expansion of repeat sequences in the DMPK and ZNF9 genes, respectively. The expansions are highly unstable and biased for further expansion in somatic cells and across generations. Despite the different genes involved, DM1 and DM2 share several clinical features due to having the similar underlying mechanism of repetitive RNA-mediated toxicity. Both disorders manifest as multisystemic conditions with features including myotonia, cataract development, and abnormalities in cardiac conduction. At present, there is no cure for DM and treatments mostly aim at symptom management. Among the therapeutics being developed, antisense therapy using gapmers is one of the most promising. Compared to other antisense oligonucleotides, gapmers maintain the ability to induce RNase H cleavage while having enhanced target binding affinity and nuclease resistance. This chapter will consolidate the different strategies studied thus far to develop a treatment for DM1 through the targeting of toxic repetitive RNA using gapmers.
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PMID:Degradation of Toxic RNA in Myotonic Dystrophy Using Gapmer Antisense Oligonucleotides. 3286 85