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Optimization of trans-Splicing for Huntington's Disease RNA Therapy.


ABSTRACT: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon 1 of the Huntingtin (HTT) gene. We have previously demonstrated that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically reduce and repair mutant HTT (mtHTT). Here, the targeted tethering efficacy of the pre-mRNA trans-splicing modules (PTM) in HTT was optimized. Various PTMs that targeted the 3' end of HTT intron 1 or the intron 1 branch point were shown trans-splice into an HTT mini-gene, as well as the endogenous HTT pre-mRNA. PTMs that specifically target the endogenous intron 1 branch point increased the trans-splicing efficacy from 1-5 to 10-15%. Furthermore, lentiviral expression of PTMs in a human HD patient iPSC-derived neural culture significantly reversed two previously established polyQ-length dependent phenotypes. These results suggest that pre-mRNA repair of mtHTT could hold therapeutic benefit and it demonstrates an alternative platform to correct the mRNA product produced by the mtHTT allele in the context of HD.

SUBMITTER: Rindt H 

PROVIDER: S-EPMC5641306 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Optimization of <i>trans</i>-Splicing for Huntington's Disease RNA Therapy.

Rindt Hansjörg H   Tom Colton M CM   Lorson Christian L CL   Mattis Virginia B VB  

Frontiers in neuroscience 20171010


Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon 1 of the <i>Huntingtin</i> (<i>HTT</i>) gene. We have previously demonstrated that spliceosome-mediated <i>trans</i>-splicing is a viable molecular strategy to specifically reduce and repair mutant HTT (mtHTT). Here, the targeted tethering efficacy of the pre-mRNA <i>trans</i>-splicing modules (PTM) in HTT was optimized. Various PTMs that targeted the 3' end of HTT intron 1 o  ...[more]

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