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.
Public Health Relevance Statement: Project Narrative Progressive osseous heteroplasia (POH), an extremely rare genetic disorder, with currently no effective treatment available, is characterized by abnormal and progressive development of bone in areas of the body where bone is not normally present (heterotopic ossification). Nostopharma is developing repurposed drug combinations as a promising approach to achieve a synergistic therapeutic effect, dose, and toxicity reduction of Hedgehog pathway (Hh) inhibitors for POH patients. The study will evaluate the synergistic activities of three small molecules towards altering the aberrant mesenchymal progenitor cells differentiation into bone cells and drug combination efficacy in a clinically relevant mouse model of POH.
Project Terms: 3,5 cyclic AMP synthetase; Adenyl Cyclase; Adenylyl Cyclase; adenylcyclase; Adenylate Cyclase; Algorithms; Animals; inhibitor; Biological Assay; Assay; Bioassay; Biologic Assays; bone; Bone Development; Bone Diseases; bone disorder; Calcitriol; Cell Differentiation process; Cell Differentiation; Cell Separation; Cell Isolation; Cell Segregation; Cell Separation Technology; cell sorting; Cell Survival; Cell Viability; Cells; Cell Body; Cholecalciferol; Calciol; VitD3; Vitamin D 3; Vitamin D3; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Disease; Disorder; Drug Combinations; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Equilibrium; balance; balance function; Genes; Erinaceidae; Hedgehogs; In Vitro; indexing; Methods; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Heterotopic Ossification; Ectopic Ossification; Pathologic Ossification; Pathological Ossification; Osteoblasts; Osteogenesis; Bone Formation; bone tissue formation; Legal patent; Patents; Patients; Phenotype; Placebos; Sham Treatment; sham therapy; Proteins; resistance factors; R Plasmids; Research; Role; social role; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Computer software; Software; Time; X-Ray Computed Tomography; CAT scan; CT X Ray; CT Xray; CT imaging; CT scan; Computed Tomography; Tomodensitometry; X-Ray CAT Scan; X-Ray Computerized Tomography; Xray CAT scan; Xray Computed Tomography; Xray computerized tomography; catscan; computed axial tomography; computer tomography; computerized axial tomography; computerized tomography; non-contrast CT; noncontrast CT; noncontrast computed tomography; Arsenic Trioxide; Arsenic (III) Oxide; Arsenic Sesquioxide; Arsenous Acid Anhydride; Arsenous Oxide; White Arsenic; arsenous anhydride; diarsenic trioxide; Measures; Eptastatin; Pravastatin; G(s), alpha Subunit; G(s), a Subunit; G(s)alpha; G(s)a; GTP-Binding Protein a Subunits, Gs; Gs alpha Family G-Protein; Gsa; Gas; Regulatory Ns Protein; Stimulatory Gs G-Protein; alpha Subunit Stimulatory GTP-Binding Protein; alpha-Gs; a-Gs; GTP-Binding Protein alpha Subunits, Gs; improved; Area; Phase; Histologically; Histologic; Series; Evaluation; bone cell; soft tissue; Individual; Therapeutic; Bone Tissue; subcutaneous; subdermal; skeletal; Drug Formulations; cytotoxicity; Lytotoxicity; guanine nucleotide binding protein; success; synergism; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; Rare Diseases; Orphan Disease; Rare Disorder; orphan disorder; Therapeutic Index; novel; Drug Interactions; Benefits and Risks; Positioning Attribute; Position; Skeleton; skeletons; Pharmacodynamics; response; drug development; Adverse event; Adverse Experience; Hedgehog (Hh) signal transduction pathway; hedgehog signaling; hedgehog signaling pathway; hh signaling pathway; smoothened signaling pathway; Mesenchymal Progenitor Cell; Mesenchymal progenitor; Mesenchymal Stem Cells; Effectiveness; preventing; prevent; Causality; causation; disease causation; Etiology; small molecule; Address; Dose; Detection; Measurable; in vivo; Pharmacological Treatment; Seminal; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Pathologic; Process; Therapeutic Effect; Development; developmental; Pathway interactions; pathway; preclinical study; pre-clinical study; mineralization; cost; neglect; designing; design; Outcome; Consumption; innovate; innovative; innovation; clinical relevance; clinically relevant; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; comparative effectiveness; murine model; mouse model; commercialization; effective treatment; effective therapy; osteogenic; drug candidate; Phase I Study; phase 1 study; phase II study; phase 2 study; screenings; screening; X-ray microtomography; Xray microtomography; micro CT; micro computed tomography; microtomography; microCT; Formulation; experiment; experimental research; experiments; experimental study; Drug Screening; Progressive osseous heteroplasia; rare genetic disease; rare genetic disorder; side effect; PK/PD; pharmacokinetics and pharmacodynamics; gene locus; genetic locus; genomic location; genomic locus; repurposing agent; repurposing medication; drug repurposing; inhibitor therapy; inhibitor drug; inhibitor therapeutic; antagonist; antagonism; comparison control; compare to control
