Inosine pro-drug: novel therapy for arthritis

描述（由申请人提供）：类风湿性关节炎（RA）是由促炎细胞因子和趋化因子的关节表达介导的。我们发现嘌呤降解产物肌苷通过A2a和A3联合激动作用发挥多重抗炎和免疫调节作用，抑制tnf - α、IL-1 β、IL-12、mip - α和ifn - γ的表达，增强IL-10的表达。我们最近开发了一种专有的肌苷前药，5'-肌苷单硫酸酯（IMS），它比肌苷在体内更有效，并显示出对炎症损伤的显着保护。在胶原诱导的自身免疫性关节炎小鼠模型中，IMS显著降低了关节炎的发病率和严重程度，降低了tnf - α和mip - α的表达，并几乎消除了中性粒细胞浸润和脂质过氧化。再加上游离肌苷是一种被批准的OTC营养补充剂，并且在人体中具有良好的安全性记录，我们设想其前药IMS作为治疗RA的新型药物的引入。该快速通道提案的具体目标是：I期：确定IMS逆转已建立的实验性关节炎，并与当前临床抗关节炎治疗联合有效。将IMS提供给反复注射胶原蛋白致关节炎的DBA/1J小鼠。我们的初步数据显示，在发病前引入IMS几乎具有完全的保护作用。为了确定已确定疾病的可逆性，在该模型系统中，在关节疾病发作后第35天引入IMS治疗。我们还将确定在第20天开始的为期一周的IMS脉冲治疗是否会对DBA/1J模型的关节炎发展提供持久的保护。最后，我们将建立IMS的协同作用，从第20天开始，与传统的抗关节炎治疗，包括布洛芬和甲氨蝶呤。进展到II期SBIR将需要IMS使已建立的胶原诱导关节炎的严重程度降低50%，并且IMS与布洛芬或甲氨蝶呤具有协同作用。在二期SBIR中，我们将确定IMS的临床前药代动力学、生化、血液学、组织病理学毒理学和安全药理学特征。建议的研究将为IMS的la期和lb期临床安全性试验提供基础。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is mediated by articular expression of pro-inflammatory cytokines and chemokines. We have discovered that the purine degradation product inosine exerts multiple anti-inflammatory and immunomodulatory effects via combined A2a and A3 agonism, resulting in suppressed expression of TNF-alpha, IL-1 beta, IL-12, MIP-lalpha, and IFN-gamma and enhanced expression of IL-10. We have recently developed a proprietary pro-drug of inosine, 5'-inosine monosulfate (IMS),that is more potent than inosine in vivo and shows dramatic protection against inflammatory injury. In a collagen-induced murine model of autoimmune arthritis, IMS profoundly reduced the incidence and severity of arthritis, reduced TNF-alpha and MIP-lalpha expression, and virtually eliminated neutrophil infiltration and lipid peroxidation. Coupled with the fact that free inosine is an approved OTC nutritional supplement and has an excellent record of safety in man, we envision the introduction of its prodrug IMS as a novel pharmaceutical for the treatment of RA. The Specific Aims of this Fast-Track proposal are: Phase I: Establish that IMS reverses established experimental arthritis and is effective in combination with current clinical anti-arthritic therapies. IMS will be provided to DBA/1J mice rendered arthritic by repeated injection of collagen. Our preliminary data show that introduction of IMS prior to the onset of disease is nearly fully protective. In order to establish the reversibility of established disease, IMS therapy will be introduced at day 35, after the onset of joint disease in this model system. We will also determine whether a one-week pulse of IMS therapy, initiated at day 20, will provide persistent protection against the development of arthritis in the DBA/1J model. Finally, we will establish the synergy of IMS, begun on day 20, with traditional anti-arthritic therapies, including ibuprofen and methotrexate. Progression to Phase II SBIR will require that IMS produces a 50% reduction in the severity of established collagen-induced arthritis and that IMS is synergistic with ibuprofen or methotrexate. In the Phase 2 SBIR, we will determine the pre-clinical pharmacokinetics and biochemical, hematologic, and histopathologic toxicology, and safety pharmacology profile of IMS. The proposed studies will provide the foundation for Phase la and lb clinical safety trials of IMS.