E!12079ENCEPHALON KTH
| Reference number | |
| Coordinator | Kungliga Tekniska Högskolan - Biomedical Engineering and Health Systems |
| Funding from Vinnova | SEK 1 984 474 |
| Project duration | March 2018 - February 2021 |
| Status | Completed |
| Venture | Eurostars |
Important results from the project
ENCEPHALON aims to (1) advance the preclinical development of QRX-704, an innovative treatment for Huntington’s disease (HD), and (2) characterize the clinically relevant, non-toxic alternative Huntingtin protein isoform which is formed following treatment with QRX-704 using a multidisciplinary approach consisting of state-of-the-art methods. The results will provide in vitro and in vivo Proof of Concept, PK/PD and tolerability data to support further (pre)clinical development of QRX-704.
Expected long term effects
Here we have taken an interdisciplinary approach to characterize the properites of deletion huntingtin, HTT12 . The reults show that HTT12 is completely resistant to caspase-6 cleavage in both cell-free and tissue lysis analysis, while retaining overall biochemical and structural properties similar to wild-type HTT. Our data therefore show that the antisense oligonucleotide strategy for inducing HTT12 may provide a new strategy for modulating HD pathology.
Approach and implementation
Partners 1 and 3 showed that HTT12 is fully resistant to caspase-6 cleavage while we could demonstrate preserved overall biochemical and structural properties similar to wild-type HTT. Furthermore, HTT12 is sufficient to support mouse embryonic development and maintains functionality of wild-type HTT involved in cytoskeleton activity (partners 1 and 3). Partner 1 pharmacologically induce HTT12 using antisense oligonucleotide (AON) QRX-704, resulting in the reduction of toxic N-terminal fragments.