Discovering a Disease Modifying Therapeutic to Treat Huntington's Disease

Period of Performance: 09/15/2017 - 05/31/2018

$1.3MM

Phase 2 SBIR

Recipient Firm

Chaperone Therapeutics, Inc.
DURHAM, NC 27704
Principal Investigator

Abstract

Protein misfolding and aggregation, leading to chronic inflammation, synaptic dysfunction and neuronal death are common hallmarks of neurodegenerative diseases including Alzheimer?s disease (AD) and Huntington?s disease (HD). While over 5 million Americans suffer from AD, and over 30,000 suffer from HD, current therapies target symptoms but not the underlying pathophysiology of protein misfolding, aggregation and its downstream sequalae underlying dementia and other clinical symptoms. Heat Shock Transcription Factor 1 (HSF1) is a master regulator that protects neurons from destructive effects of misfolded proteins by activating genes involved in protein folding, clearance and autophagy and by repressing genes that promote inflammation. In autopsied brain tissue from both AD and HD patients as well as in rodent models of these diseases, HSF1 protein levels are abnormally low compared to controls. We demonstrated that in HD tissues HSF1 levels are low due to its phosphorylation by protein kinase CK2, which stimulates proteasome-dependent degradation of HSF1. CK2 levels progressively increase in both HD and AD indicating that the observed reduction in AD brain may be due to this abnormal elevation of CK2. We strengthened the validation of CK2 as a therapeutic target through genetic ablation of one CK2 allele in a HD mouse model and demonstrated restoration of HSF1 levels concurrently with a reduction in pathology (insoluble mutant Huntingtin protein aggregates), pathophysiology (striatal medium spiny neuron abundance and synapses, muscle and body mass) and behavior. Although similar data do not exist in an AD mouse model, we have seen regulation of tau protein expression by HSF1 in an HD model and there is a published study demonstrating that CK2 inhibitors dampen inflammatory markers in primary astrocytes from an AD rodent model. Based on the multiple lines of evidence implicating the role of CK2 in pathogenesis and pathophysiology of AD and HD, we have focused on developing proprietary CK2 inhibitor leads as novel therapeutics for Alzheimer?s and Huntington?s disease. This application outlines specific aims to: (1) identify potent and selective CK2 inhibitors with drug-like properties (2) advance molecules that exhibit optimal pharmacokinetics, brain penetrance and target engagement in vivo in the mouse and (3) validate lead compounds for efficacy in a mouse model of Huntington?s disease. Although we have strategically focused on HD as a small start-up company, the lead development and candidate selection paradigm is applicable to AD. In summary, given that HSF1 levels are low, and CK2 levels are elevated in both HD and AD, the restoration of HSF1 levels through CK2 inhibition presents a promising route to a disease modifying therapy for Huntington?s and Alzheimer?s disease. Our own data and literature have led us to invest in therapeutic development of proprietary CK2 inhibitors to prevent protein misfolding via cellular chaperones and stemming the destructive effects of misfolded proteins leading to synapse loss, chronic inflammation and neuronal death.