A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function.

Autor:	Kim H; Department of Biological Sciences, KI for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea., Lenoir S; University Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France., Helfricht A; ProQR Therapeutics NV, Leiden, Netherlands., Jung T; Department of Biological Sciences, KI for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.; Department of Biomedical Engineering and Health Systems, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Huddinge, Sweden., Karneva ZK; ProQR Therapeutics NV, Leiden, Netherlands., Lee Y; Department of Biological Sciences, KI for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea., Beumer W; ProQR Therapeutics NV, Leiden, Netherlands., van der Horst GB; ProQR Therapeutics NV, Leiden, Netherlands., Anthonijsz H; ProQR Therapeutics NV, Leiden, Netherlands., Buil LC; ProQR Therapeutics NV, Leiden, Netherlands., van der Ham F; ProQR Therapeutics NV, Leiden, Netherlands., Platenburg GJ; ProQR Therapeutics NV, Leiden, Netherlands., Purhonen P; Department of Biomedical Engineering and Health Systems, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Huddinge, Sweden., Hebert H; Department of Biomedical Engineering and Health Systems, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Huddinge, Sweden., Humbert S; University Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France., Saudou F; University Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France., Klein P; ProQR Therapeutics NV, Leiden, Netherlands., Song JJ; Department of Biological Sciences, KI for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2022 Sep 08; Vol. 7 (17). Date of Electronic Publication: 2022 Sep 08.
DOI:	10.1172/jci.insight.154108
Abstrakt:	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 (HTTΔ12) 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 HTTΔ12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTTΔ12 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 HTTΔ12 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.
Databáze:	MEDLINE
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