Project Grant R43TR004574

SMALL MOLECULES COMBINATION THERAPY USING POLYPHARMACOLOGY APPROACH AS A NOVEL TREATMENT PARADIGM FOR RARE BONE DISEASE - THERE IS A CRITICAL NEED TO IMPROVE DRUG DEVELOPMENT STRATEGIES FOR RARE DISEASES, AS MORE THAN 7000 RARE AND NEGLECTED DISEASES CURRENTLY HAVE NO TREATMENTS AVAILABLE. AT THE SAME TIME, AS NEW DRUG THERAPIES REMAIN COSTLY AND TIME-CONSUMING, REPOSITIONING EXISTING DRUGS AND DRUG CANDIDATES OFFERS AN ALTERNATIVE APPROACH TO DEVELOPING THERAPEUTICS FOR RARE DISEASES. NOSTOPHARMA SEEKS TO ADDRESS THIS NEED BY DEVELOPING REPURPOSED DRUG COMBINATIONS AS A PROMISING APPROACH TO ACHIEVE A SYNERGISTIC THERAPEUTIC EFFECT, DOSE, AND TOXICITY REDUCTION. OUR PHASE I OBJECTIVES ARE TO DEMONSTRATE THE FEASIBILITY OF REPURPOSING A SMALL MOLECULE COMBINATION THERAPY, FORMULATED IN A PROPRIETARY WAY, TO TREAT A RARE GENETIC DISEASE- PROGRESSIVE OSSEOUS HETEROPLASIA (POH). POH IS A RARE DISEASE WITH NO EFFECTIVE DRUG-BASED THERAPY, WHERE BONE TISSUE FORMS IN THE EXTRASKELETAL SOFT TISSUE IN RESPONSE TO INACTIVATING MUTATIONS IN THE GNAS (THE STIMULATORY ALPHA SUBUNIT OF A GUANINE NUCLEOTIDE-BINDING PROTEIN) GENE LOCUS. HEDGEHOG SIGNALING (HH) HAS A SEMINAL ROLE IN MESENCHYMAL PROGENITOR FATE CHOICE AND INAPPROPRIATE DIFFERENTIATION INTO OSTEOBLASTS AND ECTOPIC BONE FORMATION IN SOFT TISSUES. NOSTOPHARMA WILL DEMONSTRATE THE FEASIBILITY TOWARDS ALTERING THE ABERRANT MESENCHYMAL PROGENITOR CELLS DIFFERENTIATION UTILIZING COMBINATIONS OF HEDGEHOG PATHWAY INHIBITORS. OUR APPROACH SIMULTANEOUSLY TARGETS THE DISTINCTIVE COMPONENTS OF THE HH PATHWAY TO ALLOW SYNERGETIC INHIBITION, WHICH CAN SIGNIFICANTLY REDUCE EFFECTIVE DOSES AND POTENTIAL SIDE EFFECTS AND OVERCOME THE DRUG RESISTANCE FACTOR THAT FREQUENTLY HINDERS THE SUCCESS OF MONOTHERAPIES. THIS PROOF OF CONCEPT WILL INVOLVE PHENOTYPIC SCREENING OF DRUG COMBINATIONS AND IN-VIVO EFFICACY IN THE POH MOUSE MODEL.