Studies that investigate, identify, de-risk, and confirm new targets for the treatment of Duchenne Muscular Dystrophy
Pfizer and Dr. Kunkel seek to investigate, identify, de-risk, and confirm newtargets for the treatement of Duchenne Muscular Dystrophy. Dr. Kunkel has previously utilized aknown dog model of Duchenne Muscular Dystrophy to characterize a pathway (and potentially specificgenes) that when perturbed prevent the onset of disease pathologies (the “CHB Dog Study”). Thispathway elucidated in the CHB Dog Study represents an exciting new target class for the treatment ofthe disease. Pfizer and Dr. Kunkel will first confirm these observations and then explore the potential topharmacologically manipulate the pathway identified, as described below:
1) CHB will knock down in the zebrafish model of Duchenne up to five (5) proposed targetsidentified from the CHB Dog Study to better understand role and potential value.
2) CHB will generate a transgenic/KO mouse for the most promising target and cross onto the mdxbackground for genetic target validation.
3) Based on the preliminary data around the role of Jag1 in the dog asymptomatic carriers, CHBwill cross a transgenic Jag1 mouse onto an mdx mouse line in order to confirm its role inameliorating the disease phenotype.
4) Pfizer will engage in pathway mapping around the identified targets (Jag1/Pitpna genes) anddetermine if any existing chemical matter in the Pfizer library would be predicted to modulate theidentified target/pathway.
5) At Pfizer’s sole discretion, Pfizer will provide the Kunkel Lab with chemical substrate, blinded asto structure, to be tested in the 4-day zebrafish model of Duchenne proposed targets identifiedfrom the CHB Dog Study. Pfizer compounds demonstrating a positive effect in the 4-day modelwill be tested in the 28-day model.6) If Pfizer in its sole discretion determines that there is appropriate justification, a study will be runby CHB in the mdx mouse model utilizing one or two Pfizer compounds, blinded as to structure,in a chronic study of exercise-induced activity and muscle force.