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  • Kim, HyeongjuKorea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea. (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-09-08
  • American Society for Clinical Investigation,2022
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-320243
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-320243URI
  • https://doi.org/10.1172/jci.insight.154108DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20221019
  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Lenoir, SophieUniv Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France. (author)
  • Helfricht, AngelaProQR Therapeut NV, Leiden, Netherlands. (author)
  • Jung, TaeyangKTH,Strukturell bioteknik,Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea.(Swepub:kth)u1iwn6iv (author)
  • Karneva, Zhana K.ProQR Therapeut NV, Leiden, Netherlands. (author)
  • Lee, YejinKorea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea. (author)
  • Beumer, WouterProQR Therapeut NV, Leiden, Netherlands. (author)
  • Horst, Geert B. van derProQR Therapeut NV, Leiden, Netherlands. (author)
  • Anthonijsz, HermaProQR Therapeut NV, Leiden, Netherlands. (author)
  • Buil, Levi C. M.ProQR Therapeut NV, Leiden, Netherlands. (author)
  • Ham, Frits van derProQR Therapeut NV, Leiden, Netherlands. (author)
  • Platenburg, Gerard J.ProQR Therapeut NV, Leiden, Netherlands. (author)
  • Purhonen, PasiKTH,Strukturell bioteknik(Swepub:kth)u1f7j409 (author)
  • Hebert, HansKTH,Strukturell bioteknik,Dept Biomed Engn & Hlth Syst, S-14152 Huddinge, Sweden.(Swepub:kth)u1h8ygcn (author)
  • Humbert, SandrineUniv Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France.;Univ Grenoble Alpes, Grenoble Inst Neurosci, INSERM, U1216,CHU Grenoble Alpes,, F-38000 Grenoble, France. (author)
  • Saudou, FredericUniv Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France.;Univ Grenoble Alpes, Grenoble Inst Neurosci, INSERM, U1216,CHU Grenoble Alpes,, F-38000 Grenoble, France. (author)
  • Klein, PontusProQR Therapeut NV, Leiden, Netherlands.;ProQR Therapeut NV, NL-2333 CK Leiden, Netherlands. (author)
  • Song, Ji-JoonKorea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea.;291 Daehakro, Daejeon 34141, South Korea. (author)
  • Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea.Univ Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France. (creator_code:org_t)

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  • In:JCI Insight: American Society for Clinical Investigation7:172379-3708

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