PERK Modulation for Huntington’s Disease Therapy

Novel specific disease-modifying PERK activator for Huntington’s disease

​​The Need

• There is no efficient therapy at present for neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington’s diseases. No disease-modifying approaches exist.
• Gene therapy-based clinical trials have failed so far, highlighting the need for other approaches.

Background

• Endoplasmic reticulum (ER) stress-induced cytotoxicity is a central underlying mechanism shared by all neurodegenerative diseases.
• 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.
• We have successfully tested PERK activation as a therapeutic approach for Huntington’s disease (HD). We determined that there is a strong induction of ER stress in neurons of the brain striatum, the cells that first degenerate in HD patients, but the UPR in these cells is insufficient.
• The proof of concept in HD suggests that a PERK activator could help boost the cellular protective mechanisms in neurodegenerative diseases.

The 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 - preliminary toxicity tested in vitro and in vivo.

Current Development Stage and Future Plans

• In the current SPARK-funded project we are applying a medicinal chemistry approach to improve the properties of MK-28.
• Iterative cycles of design and synthesis, focusing on Structure Activity relationship and solubility optimization.
• In the 5 months since starting this project we have performed preliminary ADME profiling of designed and synthesized compounds of the first iterative cycle.
• We have tested efficacy for cell rescue by the compounds from ER stress-induced apoptosis, identifying a lead compound of the first iterative cycle.
• Ongoing: Novel assays to measure compound reduction of ER stress.
• Our future plans include lead efficacy and selectivity in vitro.
• This will be followed by lead efficacy in HD model mice, PK and BBB penetration, shortterm toxicity in mice, stability.
• The lead compound will be assessed for other neurodegenerative diseases

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