Bone-targeted delivery of TGFβ inhibition for osteoarthritis

骨靶向递送 TGFβ 抑制骨关节炎

• 批准号: 10490884
• 负责人: Xuchen Aimee Duan
• 金额: $ 12.82万
• 依托单位: OTHRO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490884
• 关键词: Affinity; Alendronate; Animal Model; Animals; Arthralgia; Attenuated; Axon; Biological Process; Bone Marrow; Bone Matrix; Bone Pain; Bone Resorption; Bone remodeling; Bone structure; Caring; Cartilage; Cells; Characteristics; Chemicals; Clinic; Clinical Trials; Data; Data Set; Deformity; Degenerative polyarthritis; Deterioration; Development; Disease; Drug Combinations; Drug Delivery Systems; Economic Burden; Edema; Failure; Foundations; Frequencies; Future; Homeostasis; Inflammation; Joints; Lead; Legal patent; Lesion; Link; Magnetic Resonance Imaging; Maintenance; Medical; Metabolic; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Operative Surgical Procedures; Organ; Osteoclasts; Osteogenesis; Osteoporosis; Pain; Pathology; Patients; Persons; Pharmaceutical Preparations; Phase; Replacement Arthroplasty; Reporting; Safety; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Symptoms; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Transforming Growth Factor beta; United States National Institutes of Health; Weight-Bearing state; Work; Zoledronic Acid; arthropathies; articular cartilage; bisphosphonate; bone; cartilage degradation; cytokine; data modeling; dosage; efficacy testing; experience; improved; inhibitor; joint destruction; kinase inhibitor; knee pain; mouse model; nerve supply; novel; novel strategies; novel therapeutics; osteoarthritis pain; physically handicapped; preclinical study; prevent; receptor; side effect; subchondral bone; success; targeted delivery; therapeutic development; therapeutically effective; treatment optimization

Abstract Osteoarthritis (OA) is the most common degenerative joint disorders and the leading cause of physical disability. There is no effective disease modifying treatment for OA except the joint replacement surgery. We have revealed that aberrant subchondral bone remodeling leads to degeneration of joint articular cartilage. Elevated osteoclast resorption in the OA subchondral bone leads to excessive TGFβ1 that uncouples bone resorption and formation and resulted in deterioration of subchondral bone. Restoring the structural integrity of subchondral bone by inhibiting TGFβ activity in subchondral bone can prevent OA progression and cartilage degeneration. Pain is the most prominent symptom of OA that urged people to seek for medical care. Our preliminary study suggests that osteoclasts derived factor induces axonal extrusion and innervations in the subchondral bone and substantially contribute OA pain. Zoledronic acid, a bisphosphonate that inhibits osteoclasts activity, has been reported effective in reducing knee pain and the BMLs size. Suppressing of TGFβ signaling pathway with type I TGFβ receptor inhibitor has been demonstrated to rescue subchondral bone pathology and attenuate cartilage degeneration. However, TGFβs are multifunctional cytokines that are involved in a range of biological processes. Systemic inhibition of TGFβ signaling may lead to a failure in the maintenance of tissue homeostasis of other organs, particularly articular cartilage where TGFβ severs as a major anabolic factor. Thus, it is of great importance to develop a novel strategy that can retain or perhaps even increase the efficacy of the TGFβ inhibitor while improving its safety in the therapeutic applications. We have synthesized a novel drug that conjugates alendronate (ALN), a bisphosphonate drug, with LY 2109761 (LY), a selective TβRI and TβRII kinase inhibitor, through a metabolically cleavable linker. Utilizing the high affinity of ALN, we achieve bone targeted delivery and sustained bone release of TβR inhibitor. Moreover, we anticipate that this conjugate has superior effect in alleviating OA pain as ALN has also been known to relieve bone pain. In this application, we propose to investigate the effects of the conjugate in preventing the development of osteoarthritic pathologies as well as alleviating joint pain. We will also optimize the treatment dosage, frequency and evaluate the toxicity of the conjugate in OA animal model. The results are expected to provide a strong technological and theoretical foundation for future clinical trials.

摘要 骨关节炎（OA）是最常见的退行性关节疾病，也是导致身体残疾的主要原因。 除了关节置换手术外，没有有效的疾病改善治疗OA。我所降示 异常的软骨下骨重塑导致关节软骨的退化。破骨细胞升高 OA软骨下骨的吸收导致过度的TGFβ1，其使骨吸收和骨形成分离 导致软骨下骨的退化恢复软骨下骨的结构完整性， 抑制软骨下骨中的TGFβ活性可以预防OA进展和软骨退行性变。 疼痛是OA最突出的症状，促使人们寻求医疗护理。我们的初步研究 提示破骨细胞衍生因子诱导了软骨下骨的轴突挤出和神经支配， 导致OA疼痛。唑来膦酸是一种抑制破骨细胞活性的双膦酸盐， 据报道，在减少膝关节疼痛和BML大小方面有效。 已证明使用I型TGFβ受体抑制剂抑制TGFβ信号传导途径可挽救 软骨下骨病理学和减弱软骨退化。然而，TGFβ是多功能的， 参与一系列生物过程的细胞因子。全身性抑制TGFβ信号传导可能导致 其他器官的组织稳态维持失败，特别是关节软骨， 作为一个主要的合成代谢因子。因此，开发一种新的策略，可以保留或 甚至可能增加TGFβ抑制剂的功效，同时提高其在治疗应用中的安全性。 我们合成了一种新的药物，它将双膦酸盐药物阿仑膦酸钠（ALN）与LY 2109761偶联 (LY)是一种选择性TβRI和TβRII激酶抑制剂。利用高亲和力 实现了TβR抑制剂的骨靶向给药和骨缓释。此外，我们预计 该缀合物在缓解OA疼痛方面具有上级效果，因为ALN也已知可缓解骨痛。 在本申请中，我们提出研究缀合物在防止肿瘤发生中的作用。 骨关节炎病理以及减轻关节疼痛。我们还将优化治疗剂量、频率 并在OA动物模型中评价偶联物的毒性。预计结果将提供一个强有力的 为未来临床试验奠定技术和理论基础。