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Small molecules combination therapy using polypharmacology approach as a novel treatment paradigm for rare bone disease

使用多药理学方法的小分子联合疗法作为罕见骨病的新型治疗范例

基本信息

批准号：
10759694
负责人：
Jelena gvozdenovic Jeremic
金额：
$ 31.88万
依托单位：
NOSTOPHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10759694
关键词：
Address Adenylate Cyclase Adverse event Algorithms Animal Model Animals Area Arsenic Trioxide Benefits and Risks Biological Assay Bone Development Bone Diseases Bone Tissue Calcitriol Cell Differentiation process Cell Separation Cell Survival Cells Cholecalciferol Combined Modality Therapy Computer software Consumption Detection Development Disease Dose Drug Combinations Drug Formulations Drug Interactions Drug Screening Drug resistance Effectiveness Equilibrium Erinaceidae Etiology Evaluation Formulation GTP-Binding Protein alpha Subunits, Gs Genes Heterotopic Ossification Histologic In Vitro Individual Legal patent Measurable Measures Mesenchymal Stem Cells Methods Mus Mutation Osteoblasts Osteogenesis Outcome Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacological Treatment Pharmacotherapy Phase Phenotype Placebos Positioning Attribute Pravastatin Process Progressive osseous heteroplasia Proteins Rare Diseases Research Role Safety Seminal Series Signal Transduction Skeleton Small Business Innovation Research Grant Therapeutic Therapeutic Effect Therapeutic Index Time Toxic effect X-Ray Computed Tomography antagonist bone bone cell clinically relevant commercialization comparative effectiveness comparison control cost cytotoxicity design drug candidate drug development drug repurposing effective therapy experimental study genomic locus guanine nucleotide binding protein improved in vivo indexing inhibitor inhibitor therapy innovation microCT mineralization mouse model neglect novel novel therapeutics osteogenic pharmacokinetics and pharmacodynamics phase 1 study phase 2 study preclinical study prevent rare genetic disorder resistance factors response screening side effect skeletal small molecule smoothened signaling pathway soft tissue subcutaneous success synergism

项目摘要

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.

迫切需要改善罕见病的药物开发策略，因为 7000种罕见和被忽视的疾病目前没有治疗方法。同时作为新的药物治疗仍然昂贵和耗时，重新定位现有的药物和药物候选人为开发罕见疾病的治疗方法提供了另一种方法。 Nostopharma寻求通过开发重新用途的药物组合来解决这一需求，有希望的方法，以实现协同治疗效果，剂量和毒性降低。我们第一阶段的目标是证明重新利用小分子组合的可行性以专有方式配制的治疗罕见遗传性疾病的疗法-进行性骨质疏松症异型增生（POH）。POH是一种罕见的疾病，没有有效的药物治疗，其中骨组织在皮肤外软组织中形成，以响应GNAS中的失活突变（GNAS中的失活突变）。鸟嘌呤核苷酸结合蛋白的刺激性α亚基）基因座。刺猬信号传导（Hh）在间充质祖细胞命运选择中具有重要作用，分化成成骨细胞和在软组织中异位骨形成。诺斯托法马会证明了改变异常间充质祖细胞的可行性利用Hedgehog途径抑制剂的组合进行分化。我们的方法同时靶向Hh途径的独特组分以允许协同抑制，其可显著降低有效剂量和潜在副作用，耐药因素经常阻碍单药治疗的成功。这一概念验证将涉及药物组合的表型筛选和POH小鼠模型中的体内功效。