EXEMPLAR GENETICS, LLC — Department of Health and Human Services SBIR Phase II: NIAMS

Description

DESCRIPTIONprovided by applicantDuchenne muscular dystrophyDMDis an X linked recessive disorder caused by mutations in the DMD gene with a prevalence ofinmale birthsThe consequent loss of functional dystrophin results in the progressive degeneration of skeletal and cardiac muscleDespite significant progress in our understanding of this disease and advances in the development of new therapeutic approachesDMD remains a fatal diseaseMuch of what is known about DMD has come from studying dystrophin deficient animalsparticularly murine and canine modelsWhile useful for mechanistic studiesdystrophic mice fail to develop the muscle weakness phenotype that is typical of DMD in patientsThe canine models are more representative of human DMDbut are difficult to study due to extreme phenotypic variabilityThe canine models also suffer from a limited choice of mutationssignificant expenseand social acceptance concernsTherapeutic strategies that have shown promise in these models have yet to be successfully translated to the clinicAn animal model that more accurately and consistently replicates the clinical manifestations of human DMD is sorely neededOur objective is to create an improved model of DMD in the pigWe believe a porcine model offers several advantages over the existing modelsGene targeting is now available in pigs and would provide an opportunity to engineer patient relevant mutationsPorcine cloning technology would allow the production of genetically identical dystrophic pigs and could yield reduced variability in phenotype severityAlsopigs are less expensive to produce and easier to house than dogs and donandapos t face the same ethical concerns as companion animalsThe ultimate goal of this project is to develop and commercialize DMD targeted pigs as a model of Duchenne muscular dystrophyWe intend to accomplish this by combining gene targeting and somatic cell nuclear transfer to create a porcine model harboring a common human DMD mutationThis proposal outlines our plans for the creation and characterization of DMD targeted pigsCharacterization will include an assessment of the molecular and biochemical consequences of dystrophin deficiency as well as a functional evaluation of the skeletal and cardiac muscle phenotypeWe will also validate the DMD pig as a translational model by testing a nucleic acid based therapyThis animal model will provide the academic and commercial research communities an opportunity to better understand DMD and to develop and test new therapeutic strategiesPUBLIC HEALTH RELEVANCEThis proposal specifically outlines the developmentinitial characterizationand validation of a genetically engineered porcine model of the human diseaseDuchenne muscular dystrophyThis project is relevant to the NIHandapos s mission because it will provide a resource to stimulate discoverytherapeutic applicationand the development of new diagnostic tools