Validation of Novel Target for OA Treatment

OA 治疗新靶点的验证

• 批准号: 10055369
• 负责人: Duncan Lascelles
• 金额: $ 415.43万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055369
• 关键词: Accelerometer; Affect; American; Animal Model; Arthralgia; Arthritis; Behavioral; Canis familiaris; Cartilage; Clinical; Clinical Trials; DC101 Monoclonal Antibody; Data; Degenerative polyarthritis; Delayed-Action Preparations; Diagnostic radiologic examination; Disease; Disease Progression; Economic Burden; FDA approved; Female; Frequencies; Genetic; Genomics; Histopathology; Human; Incidence; Individual; Injury; Institution; Intra-Articular Injections; Iodoacetates; Joints; KDR gene; Laboratories; Letters; Ligands; Longevity; Magnetic Resonance Imaging; Measures; Medial; Methods; Modeling; Modification; Monoclonal Antibodies; Mus; Obesity; Opiate Addiction; Opioid; Orthopedics; Outcome; Pain; Pathologic Neovascularization; Pathology; Pathway interactions; Patients; Pharmacology; Prevalence; Property; Rattus; Research; Rewards; Role; Severities; Signal Transduction; Site; Surgeon; Symptoms; TNFSF15 gene; Testing; Transgenic Mice; Validation; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Work; blood vessel development; cancer therapy; conditioned place preference; disability; experimental study; inhibitor/antagonist; insurance claims; male; mouse model; nano; nanoformulation; novel; novel strategies; osteoarthritis pain; pain reduction; pain symptom; pre-clinical; prevent; receptor; reduce symptoms; response; side effect; small molecule; small molecule inhibitor; symptom management; symptom treatment; therapeutic target; tissue degeneration; transmission process; validation studies

ABSTRACT: Osteoarthritis (OA) affects nearly 100 million Americans. It is the most common form of arthritis and a leading cause of pain and disability. Prevalence and incidence of the disorder are predicted to increase because of increased lifespan and obesity. Symptomatic treatments are often ineffective, and/or associated with severe side effects and there is over-reliance on opioids. Recent insurance claim data indicate that >50% of OA patients are treated with opioids, and many have become opioid-dependent. Despite the fact that OA is a leading cause of disability, and imposes an annual economic burden exceeding $60 billion, there is no way as yet to cure OA or prevent its progression. There is an urgent need to identify and validate therapeutic targets for pain (symptom) management and to decrease disease progression. Results from our group and others show a dramatic increase in vascular endothelial growth factor (VEGF) expression and in new blood vessel formation in joints, both of which strongly correlate with the severity of OA joint pain. Also, genomic studies reveal that vegf expression is strongly associated with symptomatic OA progression in humans. FDA approval of several inhibitors of the VEGF pathway (i.e., for cancer treatment) has enabled significant advances in the therapy of diseases related to pathological angiogenesis. However, there are multiple VEGF ligands with redundant and compensatory roles that may contribute to OA progression and pain. Thus, targeting individual ligands may be less efficacious than targeting receptors. Specifically, VEGF ligands signal via two receptors, VEGFR-1 (known as Flt1) and VEGFR-2 (known as Flk1). Our central hypothesis is that because VEGFR-2/Flk1 is primarily responsible for cartilage tissue degeneration in OA, and VEGFR-1/Flt1 is the major driver of joint pain transmission, targeting both Flt1 and Flk1 simultaneously elicits dual function: (i) immediate symptom alleviation and (ii) inhibition of cartilage tissue degeneration. Thus, both disease progression and pain are halted. To rigorously validate our target, we will: 1) Use different types of target inhibitors - mAbs targeting Flt1 (by mAb MF1) and/or Flk1 (by mAb DC101) or pazopanib, an FDA-approved small inhibitor molecule for Flt1 and Flk1 currently being used for cancer treatment; 2) Use different species, different OA models and both male and female subjects using a Tg mouse model, two different mouse and rat OA models, and two different dog OA models; 3) Replicate the work in multiple laboratories; and 4) Test abuse liability of target engagement. The findings from our rigorous validation studies will take the field of OA research a giant step forward by developing a novel strategy for treating OA and joint pain effectively and safely in our pre-clinical OA animal model; and, in the longer term, by providing a rationale for clinical trials targeting Flt1 and Flk1 to treat OA patients.

抽象的： 骨关节炎 (OA) 影响着近 1 亿美国人。它是关节炎最常见的形式，也是导致关节炎的主要原因 疼痛和残疾。由于寿命的延长和寿命的延长，预计该疾病的患病率和发病率将会增加 肥胖。对症治疗通常无效，和/或伴有严重的副作用，并且存在过度依赖 关于阿片类药物。最近的保险索赔数据表明，> 50% 的 OA 患者接受阿片类药物治疗，其中许多人接受过阿片类药物治疗 变得阿片类药物依赖。尽管 OA 是导致残疾的主要原因，并且每年都会造成经济损失 负担超过 600 亿美元，目前还没有办法治愈 OA 或阻止其进展。迫切需要 确定并验证疼痛（症状）管理和减少疾病进展的治疗目标。结果 我们小组和其他人的研究显示血管内皮生长因子（VEGF）表达显着增加，并且新的 关节中的血管形成，两者都与 OA 关节疼痛的严重程度密切相关。另外，基因组 研究表明，vegf 表达与人类 OA 症状进展密切相关。 FDA 批准 VEGF 途径的几种抑制剂（即用于癌症治疗）使癌症治疗取得了重大进展 与病理性血管生成相关的疾病。然而，有多种 VEGF 配体具有冗余和 可能导致 OA 进展和疼痛的代偿作用。因此，靶向单个配体可能会更少 比靶向受体更有效。具体来说，VEGF 配体通过两种受体发出信号：VEGFR-1（称为 Flt1）和 VEGFR-2（称为 Flk1）。我们的中心假设是，因为 VEGFR-2/Flk1 主要负责软骨 OA 中的组织退化，VEGFR-1/Flt1 是关节疼痛传播的主要驱动因素，同时针对 Flt1 和 Flk1 同时产生双重功能：（i）立即缓解症状和（ii）抑制软骨组织退化。 因此，疾病进展和疼痛都停止了。为了严格验证我们的目标，我们将：1）使用不同类型的 目标抑制剂 - 靶向 Flt1（通过 mAb MF1）和/或 Flk1（通过 mAb DC101）的 mAb 或帕唑帕尼（FDA 批准的一种药物） Flt1和Flk1的小抑制剂分子目前用于癌症治疗； 2）使用不同品种，不同 OA 模型以及使用 Tg 小鼠模型、两种不同的小鼠和大鼠 OA 模型以及两种 不同的狗 OA 模型； 3）在多个实验室重复工作； 4) 测试目标参与的滥用责任。 我们严格的验证研究的结果将通过开发一个 OA 研究领域向前迈出一大步 在我们的临床前 OA 动物模型中有效、安全地治疗 OA 和关节疼痛的新策略；并且，在更长的时间内 术语，通过为针对 Flt1 和 Flk1 治疗 OA 患者的临床试验提供理论依据。