I01 QRX-704, a novel antisense oligonucleotide therapy, designed to prevent hd pathology while maintaining htt function. (September 2018)

• Record Type: Journal Article
• Authors: Klein, Pontus; Karneva, Zhana; Toonen, Lodewijk; Kim, Hyeongju; Caron, Nicholas; Graaf, Linda van der; Buil, Levi; Horst, Geert van der; Anthonijsz, Herma; Ham, Frits van der; Beumer, Wouter; Hayden, Michael; Song, Ji-Joon; Roon-Mom, Willeke van; Platenburg, Gerard
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 89(2018)Supplement 1
• Page Start: A88
• Page End: A88
• Publication Date: 2018-09
• Subjects: antisense oligonucleotides -- RNA therapy -- caspase-6; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2018-EHDN.237
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : 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.