Enabling Studies for the Treatment of Frozen Shoulder Using Relaxin

项目总结/摘要 冻结肩或“肩关节纤维化”是一种痛苦的和逐渐丧失的肩膀运动所造成的， 创伤、外科手术、炎症或长期关节固定。肩关节纤维化9例 在美国，每年有超过160万人寻求手术治疗。电流 治疗选择，包括关节内皮质类固醇注射，NSAID和神经阻滞剂，仅提供 患者症状的边缘和暂时缓解，并且不能解决疾病的根本原因- 纤维化胶原组织的积聚。在更严重的情况下使用手术干预，但这些 手术充满了并发症，并可能进一步加重症状。Ortholevo正在开发一种本地的 用于治疗肩关节炎的松弛素-2的可注射聚合物微粒持续释放制剂 纤维化人松弛素-2（RLX）是一种6-kDa的天然生殖激素肽， 在分娩前下调胶原蛋白的产生并上调基质金属蛋白酶。利用这股活力- tide治疗关节纤维化提供了一个前所未有的机会， 这种疾病的第一种治疗方法，以及由此产生的肩关节治疗模式的转变 关节纤维化 Ortholevo建议通过完成 以下是Direct II阶段的拟议目标：1）将我们的微粒封装工艺转移到路博润生命 科学健康，以建立产品质量标准，并评估灭菌和货架稳定性; 2）检测- 体内最小有效剂量（MED）、最大耐受剂量（MTD）和重复给药毒性 (RDT)在体内大鼠模型中的松弛素-2负载的微粒的浓度;和3）测定药代动力学（PK）和 在体内犬关节挛缩模型中负载松弛素-2的微粒的功效。为了实现这些目标， 我们已经收集了关键的初步数据，证明使用松弛素-2负载的微粒制剂 以及组建具有科学/工程专业知识的团队（例如，蛋白质治疗剂，微粒， 生物力学和冻结肩）以及翻译和商业化（例如，管理、监管、人- 制造和销售）。随着这一直接SBIR第二阶段的具体目标的成功完成， 接下来的步骤包括IND前会议，获得IND/IRB临床试验机构批准，然后是I期- 人体临床安全性试验。这些目标的实现将导致第一个标准的护理治疗， 基于逆转纤维化胶原蛋白的潜在和异常积聚的肩关节纤维化 以持续和受控的方式将治疗剂递送到疾病部位的组织。

PROJECT SUMMARY/ABSTRACT Frozen shoulder or “shoulder arthrofibrosis” is a painful and gradual loss of shoulder motion caused by trauma, surgical procedures, inflammation, or prolonged joint immobilization. Shoulder arthrofibrosis occurs in 9 million individuals in the United States with more than 1.6 million seeking surgical remedies each year. Current treatment options, including intra-articular corticosteroid injections, NSAIDs, and nerve blockers, provide only marginal and temporary relief of patient symptoms and do not address the underlying cause of the disease—the accumulation of fibrotic collagenous tissue. Surgical interventions are used in more severe cases, but these procedures are fraught with complications and can further aggravate symptoms. Ortholevo is developing a local injectable polymeric microparticle sustained release formulation of relaxin-2 for the treatment of shoulder arthro- fibrosis. Human relaxin-2 (RLX) is a 6-kDa naturally-occurring reproductive hormone peptide that temporally downregulates collagen production and upregulates matrix metalloproteases prior to childbirth. Using this pep- tide therapeutic for the treatment of arthrofibrosis provides an unprecedented opportunity to treat this disease with a first of its kind therapy and a resulting paradigm shift in the treatment of shoulder arthrofibrosis. Ortholevo proposes to advance its technology down the path of commercialization by the completion of the following Direct Phase II proposed aims: 1) Transfer our microparticle encapsulation process to Lubrizol Life Science Health in order to establish product specifications and assess sterilization and shelf-stability; 2) Deter- mine in vivo Minimum Effective Dose (MED), Maximum Tolerated Dose (MTD), and Repeated Dose Toxicity (RDT) of relaxin-2 loaded microparticles in an in vivo rat model; and 3) Determine pharmacokinetics (PK) and efficacy of relaxin-2 loaded microparticles in an in vivo canine joint contracture model. To accomplish these aims, we have collected key preliminary data demonstrating efficacy using a relaxin-2 loaded microparticle formulation as well as assembled a team with expertise in science/engineering (e.g., protein therapeutics, microparticles, biomechanics, and frozen shoulder) and translation and commercialization (e.g., management, regulatory, man- ufacturing and marketing). With the successful completion of the specific aims in this Direct Phase II SBIR pro- posal, the next steps include pre-IND meeting, attaining IND/IRB clinical site approval, followed by Phase I first- in-human clinical safety trial. Achievement of these goals will lead to the first standard of care treatment for shoulder arthrofibrosis based on reversing the underlying and abnormal accumulation of fibrotic collagenous tissue that delivers the therapeutic in a sustained and controlled manner to the site of disease.