Article Text

Download PDFPDF
I01 QRX-704, a novel antisense oligonucleotide therapy, designed to prevent hd pathology while maintaining htt function
  1. Pontus Klein1,
  2. Zhana Karneva1,
  3. Lodewijk Toonen2,
  4. Hyeongju Kim3,
  5. Nicholas Caron4,
  6. Linda van der Graaf2,
  7. Levi Buil1,
  8. Geert van der Horst1,
  9. Herma Anthonijsz1,
  10. Frits van der Ham1,
  11. Wouter Beumer1,
  12. Michael Hayden4,
  13. Ji-Joon Song3,
  14. Willeke van Roon-Mom2,
  15. Gerard Platenburg1
  1. 1ProQR Therapeutics, CK Leiden, The Netherlands
  2. 2Department of Human Genetics, Leiden University Medical Center, RC Leiden, The Netherlands
  3. 3Department of Biological Sciences, KAIST, Daejeon, Korea
  4. 4Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, Department of Medical Genetics, University of British Columbia, Vancouver, Canada


Background QRX-704 is a novel antisense oligonucleotide-based therapeutic approach, aiming to mitigate mutant Huntingtin (mHTT) toxicity, while maintaining physiological HTT function. Proteolytic cleavage of mHTT generates toxic N-terminal fragments that are hypothesized to be the main contributor to the pathogenesis of Huntington disease (HD). These fragments are formed from a cascade of proteolytic cleavages, initiated by caspase-6 cleavage at position D586. Importantly, HTT586 cleavage is required for HD-like phenotypes in the YAC128 mouse model. Moreover, mHTT cleavage in turn increases caspase-6 activity, driving pathology in a toxic forward-feedback loop. While toxicity stemming from mHTT cleavage is the primary pathogenic mechanism, data indicates that HTT loss-of-function exacerbates pathology. In addition, maintaining wild type HTT function may be critical for safety of HTT-targeted therapeutics when treating patients for a long period of time.

Aims QRX-704 functions at the pre-mRNA level by activating an alternative HTT splice-isoform (HTT Δ12), disrupting the critical HTT586 caspase-6 cleavage site, thus preventing formation of toxic N-terminal fragments. The aim of the study is to pharmacologically characterize QRX-704 for preclinical development, and describe the novel HTT Δ12 isoform.

Methods/techniques Biodistribution, tolerability, immunogenicity, and pharmacodynamic activity of QRX-704, administered by intracerebroventricular (ICV) injection was assessed in wild type and YAC128 mice. Biophysical and biochemical characterization of HTT Δ12 was performed using purified protein, with caspase-6 cleavage assays, CD-spectroscopy, and post-translational modification mapping.

Results/outcome ICV administration of QRX-704 was well tolerated and lead to efficient distribution and cellular uptake throughout the brain. QRX-704 induced formation of HTT Δ12 mRNA and protein in striatum and cortex in a dose-dependent manner. In vitro, recombinant HTT Δ12 is fully resistant to HTT586 caspase-6 cleavage and does not display major differences in biochemical and biophysical assays, compared to canonical HTT.

Conclusions QRX-704 constitutes a novel therapeutic approach to HD, potentially preventing toxicity of mHTT while maintaining HTT function.

  • antisense oligonucleotides
  • RNA therapy
  • caspase-6

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.