Discovering a Disease Modifying Therapeutic to Treat Huntington's Disease

Protein misfolding and aggregationleading to chronic inflammationsynaptic dysfunction and neuronal death are common hallmarks of neurodegenerative diseases including Alzheimer s diseaseADand Huntington s diseaseHDWhile overmillion Americans suffer from ADand oversuffer from HDcurrent therapies target symptoms but not the underlying pathophysiology of protein misfoldingaggregation and its downstream sequalae underlying dementia and other clinical symptomsHeat Shock Transcription FactorHSFis a master regulator that protects neurons from destructive effects of misfolded proteins by activating genes involved in protein foldingclearance and autophagy and by repressing genes that promote inflammationIn autopsied brain tissue from both AD and HD patients as well as in rodent models of these diseasesHSFprotein levels are abnormally low compared to controlsWe demonstrated that in HD tissues HSFlevels are low due to its phosphorylation by protein kinase CKwhich stimulates proteasome dependent degradation of HSFCKlevels progressively increase in both HD and AD indicating that the observed reduction in AD brain may be due to this abnormal elevation of CKWe strengthened the validation of CKas a therapeutic target through genetic ablation of one CKallele in a HD mouse model and demonstrated restoration of HSFlevels concurrently with a reduction in pathologyinsoluble mutant Huntingtin protein aggregatespathophysiologystriatal medium spiny neuron abundance and synapsesmuscle and body massand behaviorAlthough similar data do not exist in an AD mouse modelwe have seen regulation of tau protein expression by HSFin an HD model and there is a published study demonstrating that CKinhibitors dampen inflammatory markers in primary astrocytes from an AD rodent modelBased on the multiple lines of evidence implicating the role of CKin pathogenesis and pathophysiology of AD and HDwe have focused on developing proprietary CKinhibitor leads as novel therapeutics for Alzheimer s and Huntington s diseaseThis application outlines specific aims toidentify potent and selective CKinhibitors with drug like propertiesadvance molecules that exhibit optimal pharmacokineticsbrain penetrance and target engagement in vivo in the mouse andvalidate lead compounds for efficacy in a mouse model of Huntington s diseaseAlthough we have strategically focused on HD as a small start up companythe lead development and candidate selection paradigm is applicable to ADIn summarygiven that HSFlevels are lowand CKlevels are elevated in both HD and ADthe restoration of HSFlevels through CKinhibition presents a promising route to a disease modifying therapy for Huntington s and Alzheimer s diseaseOur own data and literature have led us to invest in therapeutic development of proprietary CKinhibitors to prevent protein misfolding via cellular chaperones and stemming the destructive effects of misfolded proteins leading to synapse losschronic inflammation and neuronal death Narrative Huntingtonandapos s diseaseHDis a fataldebilitating neurodegenerative disorder that carries a large mortality and morbidity burden and profoundly impacts patientsandaposquality of lifeAlthough uncommonthe number of people with HD in North America and Europe alone is estimated to be betweenandThere is a clear need for newcost effective therapeutics which will provide a disease modifying regimen that is safe and well tolerated