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Efficacy of therapy by MK-28 PERK activation in the Huntington's disease R6/2 mouse model
Talya Shacham1, Daniel Offen2, Gerardo Z Lederkremer3
1The Shmunis School of Biomedicine and Cancer Research, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
Abstract:
There is currently no disease-modifying therapy for Huntington's disease (HD). We recently described a small molecule, MK-28, which restored homeostasis in HD models by specifically activating PKR-like ER kinase (PERK). This activation boosts the unfolded protein response (UPR), thereby 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 intraperitoneal injections 3 times a week. CatWalk measurements of motor function showed strong improvement compared to untreated mice 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 reduced. Treatment with another PERK activator, CCT020312 at 1 mg/kg, also caused amelioration, consistent with PERK activation. Lifespan, measured in more resilient R6/2 CAG (120) mice with daily IP injection, was much 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 could be a safe and promising therapeutic approach for HD.
Insights
MK-28, a novel molecule, shows promise for Huntington's disease (HD) by activating PKR-like ER kinase (PERK). Long-term studies in HD mice demonstrate improved motor function, strength, and extended lifespan without toxicity, suggesting a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Huntington's disease (HD) currently lacks disease-modifying therapies.
- Endoplasmic reticulum (ER) stress is a key cytotoxic mechanism in HD and other neurodegenerative diseases.
- PKR-like ER kinase (PERK) activation can mitigate ER stress.
Purpose of the Study:
- To evaluate the long-term therapeutic effects of the PERK activator MK-28 in mouse models of Huntington's disease.
- To assess the safety and efficacy of MK-28 for improving motor function, metabolic parameters, and lifespan in HD models.
Main Methods:
- Lifetime intraperitoneal injections of MK-28 were administered to R6/2 CAG (160) HD model mice.
- Motor function was assessed using CatWalk gait analysis and paw grip strength measurements.
- Lifespan was measured in R6/2 CAG (120) mice treated daily with MK-28.
- Safety was evaluated in wild-type (WT) mice by monitoring weight, blood glucose, and liver function markers.
Main Results:
- MK-28 treatment significantly improved motor function and paw grip strength in HD mice, approaching wild-type values.
- Elevated glucose levels in HD mice were reduced by MK-28 treatment.
- Lifespan was substantially extended in HD mice treated with MK-28, with a 46% increase at the higher dose.
- No discernible toxicity was observed in WT mice treated with high doses of MK-28.
Conclusions:
- Long-term activation of PERK by MK-28 offers a potentially safe and effective therapeutic strategy for Huntington's disease.
- MK-28 demonstrates significant improvements in key pathological and functional outcomes in HD mouse models.
- Further investigation into MK-28 as a disease-modifying therapy for HD is warranted.
