Validation of Novel Target for OA Treatment

摘要： 骨关节炎（OA）影响近1亿美国人。它是关节炎最常见的形式，也是关节炎的主要原因。 疼痛和残疾。由于寿命的延长，这种疾病的患病率和发病率预计会增加， 肥胖对症治疗通常无效，和/或与严重的副作用有关，并且过度依赖 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，其中许多患者 变得依赖阿片类药物尽管OA是导致残疾的主要原因，并且每年都造成经济损失， 尽管负担超过600亿美元，但目前还没有办法治愈OA或预防其进展。迫切需要 确定和验证疼痛（症状）管理的治疗靶点，并减少疾病进展。结果 来自我们小组和其他人的研究显示，在新生血管中，血管内皮生长因子（VEGF）的表达显著增加， 关节中的血管形成，这两者都与OA关节疼痛的严重程度密切相关。此外，基因组 研究揭示VEGF表达与人类中有症状的OA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）已经使得在癌症治疗中的显著进步成为可能。 与病理性血管生成有关的疾病。然而，存在多种VEGF配体，其具有冗余和不稳定性。 可能导致OA进展和疼痛的代偿作用。因此，靶向单个配体可能更少， 比靶向受体更有效。具体地，VEGF配体通过两种受体VEGFR-1（称为Flt1）和 VEGFR-2（称为Flk1）。我们的中心假设是，由于VEGFR-2/Flk1主要负责软骨 OA中的组织变性，VEGFR-1/Flt1是关节疼痛传递的主要驱动因素，靶向Flt1和Flk1 同时增强双重功能：（i）立即缓解症状和（ii）抑制软骨组织变性。 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 靶向抑制剂-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 目前用于癌症治疗的Flt1和Flk1的小抑制剂分子; 2）使用不同的物种，不同的 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小鼠和大鼠OA模型， 不同的狗OA模型; 3）在多个实验室中重复工作;以及4）测试目标参与的滥用倾向。 我们严格验证研究的结果将使OA研究领域向前迈出一大步， 在我们的临床前OA动物模型中有效和安全地治疗OA和关节疼痛的新策略;并且，在更长的时间内， 术语，通过为靶向Flt1和Flk1治疗OA患者的临床试验提供理论基础。

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.