Novel specific disease-modifying PERK activator for Huntington’s disease
There is no efficient therapy at present for Huntington’s disease (HD) nor for any other neurodegenerative disease, including Alzheimer’s and Parkinson’s diseases. No disease-modifying approaches exist.
Gene therapy-based clinical trials have failed so far, highlighting the need for other approaches. These include the recent interruption of antisense oligonucleotide clinical trials for HD.
• 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.
• 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.
Pending. National phase in Europe and the US.
Ganz J, Shacham T, Kramer M, Shenkman M, Eiger H, Weinberg N, Iancovici O, Roy S, Simhaev L, Da'adoosh B, Engel H, Perets N, Barhum Y, Portnoy M, Offen D, Lederkremer GZ. A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models. Sci Rep. 10(1):6875. doi: 10.1038/s41598-020-63899-4. (2020)