Novel Therapy for Huntington's Disease

Novel Therapy for Huntingtonandapos s DiseaseHDPIMichael PVitekPh DPolyglutamine repeat diseasesa group of at least eight disorders including Huntingtonandapos s diseaseHDresult from the expression of mutant proteins containing an expanded polyglutamine domainZoghbi and BotasThe pathological length huntingtinHttprotein in HD aggregates in the cytoplasm and nucleus to kill cellsparticularly medium spiny neurons of the striatumSchilling et alSieradzan and MannSince not all neurons die from expression of pathological Htt proteinsthe exact mechanism of death is still unclearbut several potential mechanisms have been put forwardBased on our preliminary cell culture data that were published in the Journal of NeuroscienceColton et alwe are focused on the arginine polyamine pathway as a key mechanism underlying the pathology of HDUsing this focuswe showed that DiFluoroMethylOrnithineDFMOeffectively reduced a number of HD characteristics including the aggregation of pathological length poly glutamine Huntingtin proteins and reduced neuronal cell death resulting from expression of pathological length poly glutaminepoly QHuntingtin proteinsWith these published findings supporting the principlethis proposal seeks to define aProof ofConceptin animals that DFMO treatment will improve several key outcomes in the progression of a Huntingtonandapos s like disease in transgenic Huntingtonandapos s mice expressing a pathological length poly Q Huntingtin proteinIf we can successfully demonstrate utility of DFMO in this mouse HD modelthen in future proposalswe would expand our efforts to create and test novelpatentable prodrugs of DFMO in a mouse model of HDSince DFMO was a drug approved by the FDA for use in humansand is currently not marketed because it is off patentour patent pending DFMO prodrugs would offer a more rapid regulatory path for clinical development of a novel therapy for HD patients Novel Therapy for Huntingtonandapos s DiseaseHDPIMichael PVitekPh DHuntingtonandapos s DiseaseHDis characterized by progressive loss of motor function and eventually death of the patientIn preliminary studieswe published that DFMOan FDA approved drug that is no longer marketedwas effective in improving outcomes associated with HDIn this proposalwe seek support of aProof of Conceptthat DFMO will improve outcomes in a mouse model of HDIf the concept is proventhen we will expand our efforts to make patentable prodrugs of DFMO for use in HD patients