AUTHOR=Rindt Hansjörg , Tom Colton M. , Lorson Christian L. , Mattis Virginia B. 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=11

YEAR=2017

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2017.00544

DOI=10.3389/fnins.2017.00544

ISSN=1662-453X

ABSTRACT=<p>Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in exon 1 of the <italic>Huntingtin</italic> (<italic>HTT</italic>) gene. We have previously demonstrated that spliceosome-mediated <italic>trans</italic>-splicing is a viable molecular strategy to specifically reduce and repair mutant HTT (mtHTT). Here, the targeted tethering efficacy of the pre-mRNA <italic>trans</italic>-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 <italic>trans</italic>-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 <italic>trans</italic>-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 mt<italic>HTT</italic> allele in the context of HD.</p>