Preclinical studies to validate the efficacy of novel mechanism-of-action small molecule inhibitors to treat Duchenne muscular dystrophy

Progressive muscle weakness and degeneration is a hallmark of Duchenne muscular dystrophyDMDIn DMD patientsthe lack of dystrophin reduces muscle fiber structural integritymaking muscles vulnerable to persistent injury and damageRepairing these damaged muscles requires the continual activation of muscle stem cellsmuSCwhich leads to muSC dysfunction and senescenceand ultimately the muscle degeneration and weakness phenotype observed in DMD patientsUnfortunatelyexisting FDA approved drugseteplirsendeflazacortdo not sufficiently improve muscle regenerationand appear to provide only marginal improvements in muscle function and quality of life for DMD patientsRidgeline Therapeutics has developed novel orally bioavailable small molecule NNMTnicotinamide N methyltransferaseinhibitorse gRTLthat reactivate dysfunctional and senescent muSCWhile initially developed as a therapeutic to reverse age related muscle degenerationrecent in vivo studies suggest the NNMT inhibitor RTLcould improve muscle regeneration and function in DMD patientsThis project will expand on our preliminary research and complete proof of concept studies to rigorously test the efficacy of RTLtwo complementary DMD mouse modelsOverexpression of NNMT interferes with the NAD salvage pathwaymuSC regenerative functionand cellular metabolismincluding mitochondrial bioenergeticsSkeletal muscles of DMD patients have greatly increased expression of NNMTsuggesting NNMT could be a vital contributing factor to muSC dysfunction and metabolic dysregulation observed in DMD patientsAs a potential DMD treatmentRLTfunctions by selectively inhibiting NNMTresulting in increased muSC activityenhanced mitochondrial functionand ultimately improved muscle strength and functionThese unique mechanisms of action makes RLTand other NNMT inhibitors in our pipelinedistinct from the few DMD therapeutics that are FDA approved or in earlystage clinical trialsThis Phase I STTR project will build upon our encouraging in vivo DMD efficacy studies and test the effectiveness of RLTin more advanced and translationally relevant murine models of DMDThe following two Aims will be completed to assess the potential of RLTto serve as an oral DMD drugAimwill complete an oral chow admixed pharmacokineticPKstudy to assess plasma profiles of RLTand compare to systemic exposures observed via oral gavage administration of the drugThis PK study will validate the optimal drug delivery route for longitudinal efficacy studies in DMD miceAimwill complete in vivo dose ranging efficacy studies using Bmdx and Dmdx mice models of DMDevaluating muSC activitymitochondrial functiondiaphragm contractile functionand fibrosis ex vivoand in vivo functional endpointse gmuscle strengthenduranceand grip strengthFollowing successful demonstration of the therapeutic effects of RTLin animal modelsRidgeline will rapidly advance RTLto clinical trials as a potential DMD treatmentsince RLTis in GMP scale up and GLP safety studies for a separate clinical indication PROJECT NARRATIVE This project will complete critical dose ranging in vivo proof of concept efficacy studies using translationally relevant mouse models to significantly derisk our novel small molecule therapeutic lead that selectively targets nicotinamide N methyltransferases to effectively regenerate muscleimprove muscle mitochondrial functionand enhance muscle strength and function in Duchene muscular dystrophy