Targeting RAS Gene Pathways in Psoriatic Arthritis

 描述（由申请人提供）：银屑病关节炎（PsA）是一种慢性炎症性疾病，可导致侵蚀性关节损伤。尽管治疗方面的进展，包括新生物制剂的可用性，改善了结果，但许多患者仍然对现有疗法没有反应，并遭受严重的关节损伤，从而导致残疾。PsA的发病机制仍然知之甚少，这是开发新的和更有效的治疗方法的障碍。我们已经产生了初步的数据表明，RAS通路中的基因在PsA患者中上调。与其他炎症性疾病如类风湿性关节炎（RA）患者相比，PsA的RAS相关基因特征似乎是不同的，这表明PsA中存在独特的靶点，可以进行治疗性阻断。此外，已知激活RAS基因参与某些恶性肿瘤，并与炎症介质（包括参与PsA发病机制的细胞因子）的产生增强相关。靶向PsA中的RAS特别有吸引力，因为抑制该途径中的信号传导的小分子药物正在开发用于治疗恶性肿瘤和其他疾病。这些可能被重新用于治疗PsA患者。我们建议建立RAS签名与PsA的临床特征的相关性，并测试离体RAS抑制对PsA患者血细胞的影响，检查对炎性细胞因子产生的影响。该探索性项目的结果将用于确定在PsA患者中体内测试RAS抑制作用的可行性。

 DESCRIPTION (provided by applicant): Psoriatic arthritis (PsA) is a chronic inflammatory condition that causes erosive joint damage. Although advances in treatments, including availability of new biologics, have improved outcomes, many patients still do not respond to available therapies and suffer significant joint damage with resultant disability. The pathogenesis of PsA remains poorly understood and this is an impediment to development of new and more effective therapeutics. We have generated preliminary data suggesting that genes in the RAS pathway are upregulated in patients with PsA. The RAS-related gene signature appears to be distinct for PsA compared to patients with other inflammatory conditions such as rheumatoid arthritis (RA), suggesting that there are unique targets in PsA which would be amenable to therapeutic blockade. Furthermore, activating RAS genes are known to be involved in some malignancies and are associated with enhanced production of inflammatory mediators including cytokines that are implicated in PsA pathogenesis. Targeting RAS in PsA is especially attractive because small molecule drugs that inhibit signaling in this pathway are in development for treatment of malignancies and other diseases. These might be repurposed to treat PsA patients. We propose to establish the correlations of the RAS signature with clinical features of PsA and to test ex vivo the effects of RAS inhibition on blood cells from PsA patients, examining effects on production of inflammatory cytokines. Results of this exploratory project will be used to determine feasibility of testing in vivo the effects of RAS inhibition in patients with PsA.