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Novel Specific Disease-modifying PERK Activator for Huntington's Disease
Ramot At Tel Aviv University
Small molecule
Neurology
Pre-Clinical
Background
• Endoplasmic reticulum (ER) stress-induced cytotoxicity is a central underlying mechanism shared by all neurodegenerative diseases
• The Lederkremer group was the first to determine that there is a strong induction of ER stress in neurons of the brain striatum, the cells that first degenerate in HD patients
• ER stress induces the unfolded protein response (UPR), which activates several pathways, one initiated at the ER membrane by the PERK kinase
• This response is initially cell protective but can be cytotoxic in the long-term. Initial approaches based on inhibition of the PERK pathway failed
• As the Lederkremer lab found that striatal neurons have a very low PERK activity, a PERK activator could help boost the cellular protective mechanisms upon HD onset
Invention
• A novel small molecule activator of the PERK sensor of the UPR called MK-28 was developed
• MK-28 showed excellent efficacy - compensates for ER stress induced cytotoxicity and rescues HD cellular and mouse models from cell death
• Motor function is significantly improved and life expectancy is extended in HD mouse models
• MK-28 is specific - selectivity for PERK was shown in a kinase panel with purified components and lack of activity in PERK knockout cells
• MK-28 is a small BBB-penetrating molecule with a favorable pharmacokinetics profile
• MK-28 is non-toxic and safe - tested in vitro and in vivo
Portnoy Moshe, LEDERKREMER Gerardo Zelmar, Offen Daniel
US 10723706 B2 (2020.07.28)
Patent Family: PCT, US, EP
"A novel specific PERK activator reduces toxicity and extends survival in Huntington’s disease models". Ganz, J. et al. Scientific Reports 2020, 10(1)
"Efficacy of therapy by MK-28 PERK activation in the Huntington’s disease R6/2 mouse model". Shacham T et al. PREPRINT. Res. Square. 2023
