Efficacy of therapy by MK-28 PERK activation in the Huntington's disease R6/2 mouse model

Abstract

There is currently no disease-modifying therapy for Huntington’s disease (HD) and two recent clinical trials testing antisense oligonucleotides failed. We recently described a small molecule, MK-28, which restored homeostasis in HD models by specifically activating PKR‐like ER kinase (PERK) and thus boosting neuroprotection by the unfolded protein response (UPR), and reducing endoplasmic reticulum (ER) stress, a central cytotoxic mechanism in HD and other neurodegenerative diseases. Here we have tested the long-term effects of MK-28 in HD model mice. R6/2 CAG (160) mice were treated by lifetime IP injection, 3 times a week. CatWalk measurements of motor function showed significant improvement after only two weeks of MK-28 treatment and continued with time, most significantly at 1 mg/kg MK-28, approaching WT values. Seven weeks treatment significantly improved paw grip strength. Body weight recovered and glucose levels, which are elevated in HD mice, were significantly lowered. Treatment with another PERK activator, CCT020312, also caused amelioration, although less significant than with MK-28 in some of the parameters. Lifespan, measured in more resilient R6/2 CAG (120) mice with daily IP injection, was significantly extended by 16 days (20%) with 0.3 mg/kg MK-28, and by 38 days (46%) with 1 mg/kg MK-28. No toxicity, measured by weight, blood glucose levels and blood liver function markers, was detectable in WT mice treated for 6 weeks with 6 mg/kg MK-28. Boosting of PERK activity by long-term treatment with MK-28 appears to be a safe and promising therapeutic approach for HD.