S1B-2 Therapeutics and Biomarker Development in Huntington’Disease

Most neurodegenerative diseases,including Alzheimer’s,Parkinson’s,and Huntington’s disease(HD),have converging pathogenesis,such as formation of abnormal protein aggregates and mitochondrial dysfunction.Unfortunately,despite tremendous efforts by many scientists and increasing knowledge about disease mechanisms,we still lack disease-modifying treatments for any of these diseases.Drug discovery has been revolutionized in the past decade.Despite technological advances as a result of substantial investment,the number of new drug approvals remains stagnant and the cost of bringing a drug to market is higher than ever.This highlights the persistence of a model of drug development that has not adapted to changes in science and public perception of drug companies.While these diseases affect different areas of the brain and are distinct at the cellular and molecular levels,they share many underlying similarities.Thus,development of treatment for any of these diseases may provide clues to accelerate the path to the treatment for other neurodegenerative diseases.Research into potential therapies for HD is particularly attractive because it is a genetically homogeneous disease for which well-established models exist.The HD gene encodes the protein huntingtin(Htt),whose polyglutamine expansion is believed to mediate the cytotoxic effects of HD.Therefore,HD also serves a model for polyglutamine diseases.HD is a monogenic neurodegenerative disorder caused by mutation of the gene Huntingtin.Htt lowering(gene silencing)strategies,including antisense oligonucleotides,shRNA,miRNA et al,have shown great preclinical promise,and the first HTT lowering clinical trial is underway.The key to success of these trials will be to know where and when to intervene,since these reagents do not penetrate the blood-brain-barrier,and must be delivered directly to the CNS.HD is notable for preferential atrophy of the striatum but also involves degeneration in cortex,subcortical white matter,and specific subcortical grey matter regions.It has been shown regional spread of pathology in the HD brain using neuroimaging.In addition,neurodegeneration in HD is mainly caused by toxic effects of the abnormal Htt protein,and there is increasing evidence that mutant Htt can spread,like prions.A better understanding of HD pathology at a cellular level and in the network context would be important for determining the optimal timing and brain regional location of therapeutic interventions.HD mouse models provide unique values to answer these questions,as brain samples can be collected at a temporal manner from different disease stages(before disease onset,at the onset,after the onset)in a relatively short period.Knowledge of HD pathogenesis is bearing fruit in experimental treatments,using agents to decrease production of the huntingtin message RNA and protein.An understanding of how pathology of HD may spread throughout the brain can be guided by an understanding of the cortico-basal-ganglionic circuitry.Selective pathology within the basal ganglia circuit may contribute to features of HD phenotype.