Long-Term Safety, Efficacy, and Mechanism of PERK Inhibition Therapy for Prion Disease

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Project Summary Background There are currently no therapies that can stop the process of neuronal degeneration in diseases associated with protein misfolding such as prion disease, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that the kinase PERK, a critical regulator of the unfolded protein response (UPR), triggers both neurodegeneration and neuroinflammation in response to protein misfolding. GSK2606414, an orally bioavailable PERK inhibitor, successfully delayed the progression of infectious prion disease in mice over a 3-week observation period even when administered after the onset of symptoms (9/9 mice treated with the drug survived prion infection, while 0/17 untreated mice died). However, this promising drug inhibits PERK in pancreatic β-cells as well as the brain, and so causes hyperglycemia as a side effect. Although hyperglycemia can be easily managed in humans, it is much more difficult to control in experimental mice, and therefore the trial had to be abandoned after three weeks. Consequently we do not know whether inhibiting PERK could successfully treat prion disease for extended periods of time in mice. This information is critical before planning clinical trials of the drug in humans. Proposed Experiments In Specific Aim 1, we will use transgenic mice expressing tamoxifen-inducible CRE recombinase under the control of the Thy1 promoter to knock out PERK in all neurons, but not in pancreatic β-cells. Hyperglycemia will not occur, and therefore we will be able to complete the extended trial of PERK inhibition that could not be completed before. We will determine the long-term safety of PERK inhibition, and its efficacy in the treatment of prion infection in mice. This study will show whether anti- PERK drugs have potential for use as a long-term treatment for prion diseases, and potentially as long-term prophylaxis in individuals with familial prion disease. Our approach represents a cost- effective and time-efficient way to answer these important questions. In Specific Aim 2, we will use transgenic mice with PERK selectively knocked out of astrocytes and microglia to determine whether PERK-mediated neuroinflammation also contributes to the mechanism of neuronal death in prion disease. In summary, our experiments will provide important information about the safety, effectiveness, and mechanism of PERK inhibition as a long-term therapy against neurodegeneration.