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Replacement of huntingtin exon 1 by trans-splicing

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Abstract

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a “gain-of-function” mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans-splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans. We detected the presence of the trans-spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans-spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre-mRNA trans-splicing may be a promising approach for the treatment of HD and other dominant genetic disorders.

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Acknowledgments

This work was supported by a Faculty Research grant from the University of Missouri College of Veterinary Medicine, the Huntington Disease Foundation of Canada, and the National Institutes of Health (1R21NS070072).

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Authors and Affiliations

  1. Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO, 65211, USA

    Hansjörg Rindt, Pei-Fen Yen & Christian L. Lorson

  2. Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA

    Christina N. Thebeau & Gary A. Weisman

  3. Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, 65211, USA

    Troy S. Peterson & Gary A. Weisman

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  1. Hansjörg Rindt
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Correspondence to Christian L. Lorson.

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18_2012_1083_MOESM1_ESM.pptx

Supplementary Fig. 1 Sequence of the trans-splicing product. The F2-R4 product shown in Fig. 3 was cloned and sequenced to confirm correct splicing. Exon junctions are indicated by the thick vertical bars. (PPTX 95 kb)

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Rindt, H., Yen, PF., Thebeau, C.N. et al. Replacement of huntingtin exon 1 by trans-splicing. Cell. Mol. Life Sci. 69, 4191–4204 (2012). https://doi.org/10.1007/s00018-012-1083-5

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