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A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function
Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea..ORCID iD: 0000-0001-8668-0323
Univ Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France..ORCID iD: 0000-0002-4474-033X
ProQR Therapeut NV, Leiden, Netherlands..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology. Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea..ORCID iD: 0000-0003-3862-3433
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2022 (English)In: JCI Insight, ISSN 2379-3708, Vol. 7, no 17, article id e154108Article in journal (Refereed) Published
Abstract [en]

Huntington's disease (HD) is a late-onset neurological disorder for which therapeutics are not available. Its key pathological mechanism involves the proteolysis of polyglutamine-expanded (polyQ-expanded) mutant huntingtin (mHTT), which generates N-terminal fragments containing polyQ, a key contributor to HD pathogenesis. Interestingly, a naturally occurring spliced form of HTT mRNA with truncated exon 12 encodes an HTT (HTT & UDelta;12) with a deletion near the caspase-6 cleavage site. In this study, we used a multidisciplinary approach to characterize the therapeutic potential of targeting HTT exon 12. We show that HTT & UDelta;12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTT & UDelta;12 retained overall biochemical and structural properties similar to those of wt-HTT. We generated mice in which HTT exon 12 was truncated and found that the canonical exon 12 was dispensable for the main physiological functions of HTT, including embryonic development and intracellular trafficking. Finally, we pharmacologically induced HTT & UDelta;12 using the antisense oligonucleotide (ASO) QRX-704. QRX-704 showed predictable pharmacology and efficient biodistribution. In addition, it was stable for several months and inhibited pathogenic proteolysis. Furthermore, QRX-704 treatments resulted in a reduction of HTT aggregation and an increase in dendritic spine count. Thus, ASO-induced HTT exon 12 splice switching from HTT may provide an alternative therapeutic strategy for HD.

Place, publisher, year, edition, pages
American Society for Clinical Investigation , 2022. Vol. 7, no 17, article id e154108
National Category
Endocrinology and Diabetes Neurosciences Neurology
Identifiers
URN: urn:nbn:se:kth:diva-320243DOI: 10.1172/jci.insight.154108ISI: 000863210100001PubMedID: 35943803Scopus ID: 2-s2.0-85137662360OAI: oai:DiVA.org:kth-320243DiVA, id: diva2:1704641
Note

QC 20221019

Available from: 2022-10-19 Created: 2022-10-19 Last updated: 2022-10-19Bibliographically approved

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Jung, TaeyangPurhonen, PasiHebert, Hans

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Kim, HyeongjuLenoir, SophieJung, TaeyangPurhonen, PasiHebert, Hans
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