Enabling Studies for the Treatment of Frozen Shoulder Using Relaxin

使用松弛素治疗肩周炎的研究

基本信息

批准号：
10448418
负责人：
Edward Ahn
金额：
$ 91.48万
依托单位：
ORTHOLEVO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448418
关键词：
Achievement Address Adrenal Cortex Hormones Affect Anesthesia procedures Animal Model Animals Ankle Articular Range of Motion Biodistribution Biological Sciences Biomechanics Birth Canis familiaris Chemistry Childbirth Clinical Collaborations Collagen Contracture Data Development Plans Diabetes Mellitus Disease Distal Dose Down-Regulation Drug Delivery Systems Drug Kinetics Effectiveness Engineering Ensure Experimental Designs Fibroblasts Fibrosis Formulation Freezing Frequencies General Population Goals Half-Life Health Sciences Hip region structure Histologic Human Immobilization In Vitro Incidence Individual Inflammation Injectable Injections Institutional Review Boards Intra-Articular Injections Joints Knee Marketing Maximum Tolerated Dose Metalloproteases Microspheres Modeling Morphology Motion Motivation Nerve Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Organ Pain Patients Peat Performance Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Physical therapy Polymers Procedures Process Production Property Proteins Protocols documentation Rattus Relaxin Risk Rogaine Safety Schedule Science Shoulder Site Small Business Innovation Research Grant Sterilization Symptoms Technology Testing Therapeutic Tissues Toxic effect Translations Trauma United States Wrist articular cartilage base clinical investigation clinical research site commercialization efficacy study first-in-human improved in vivo individualized medicine joint function manufacturing process meetings particle peptide drug peptide hormone preclinical evaluation product development reduce symptoms reproductive hormone standard of care therapeutic protein

Achievement Address Adrenal Cortex Hormones Affect Anesthesia procedures Animal Model Animals Ankle Articular Range of Motion Biodistribution Biological Sciences Biomechanics Birth Canis familiaris Chemistry Childbirth Clinical Collaborations Collagen Contracture Data Development Plans Diabetes Mellitus Disease Distal Dose Down-Regulation Drug Delivery Systems Drug Kinetics Effectiveness Engineering Ensure Experimental Designs Fibroblasts Fibrosis Formulation Freezing Frequencies General Population Goals Half-Life Health Sciences Hip region structure Histologic Human Immobilization In Vitro Incidence Individual Inflammation Injectable Injections Institutional Review Boards Intra-Articular Injections Joints Knee Marketing Maximum Tolerated Dose Metalloproteases Microspheres Modeling Morphology Motion Motivation Nerve Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Organ Pain Patients Peat Performance Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Physical therapy Polymers Procedures Process Production Property Proteins Protocols documentation Rattus Relaxin Risk Rogaine Safety Schedule Science Shoulder Site Small Business Innovation Research Grant Sterilization Symptoms Technology Testing Therapeutic Tissues Toxic effect Translations Trauma United States Wrist articular cartilage base clinical investigation clinical research site commercialization efficacy study first-in-human improved in vivo individualized medicine joint function manufacturing process meetings particle peptide drug peptide hormone preclinical evaluation product development reduce symptoms reproductive hormone standard of care therapeutic protein

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项目摘要

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.

项目摘要/摘要冷冻的肩膀或“肩关节纤维化”是由创伤，外科手术，炎症或长时间的关节固定。肩关节纤维化发生在9 在美国，有超过160万人寻求手术疗法的百万个人。当前的治疗选择，包括关节内皮质类固醇注射，NSAID和神经阻滞剂，仅提供边际和暂时缓解患者症状，并且没有解决该疾病的根本原因 - 纤维化胶原组织的积累。在更严重的情况下使用了手术干预措施，但是过程充满并发症，可以进一步加剧符号。 Ortholevo正在开发本地可注射的聚合微粒持续的释放蛋白-2释放公式用于治疗肩部artro- 纤维化。 Human Lexein-2（RLX）是一种6 kDa，自然呈现的生殖马肽下调胶原蛋白的产生，并在分娩之前上调基质金属蛋白酶。使用这个pep- 治疗关节纤维化治疗的潮汐疗法为治疗这一点提供了前所未有的机会疾病，首先具有这种疗法，并在肩膀治疗中范围内转变节肢动物。 Ortholevo的提议通过完成遵循直接II期提出的目的：1）将我们的微粒封装过程转移到Lubrizol Life 科学健康是为了建立产品规格和评估灭菌和固定稳定性； 2）阻止 - 我的体内最低有效剂量（MED），最大耐受剂量（MTD）和重复剂量毒性在体内大鼠模型中加载的弛豫蛋白2的（RDT）； 3）确定药代动力学（PK）和在体内犬关节缔合模型中，释放蛋白2加载的微粒的功效。为了实现这些目标，我们已经收集了关键的初步数据，证明了使用helalein-2加载的微粒公式的效率除了组建一个具有科学/工程专业知识的团队（例如，蛋白质治疗，微粒，生物力学，肩膀冷冻）以及翻译和商业化（例如，管理，监管，人类 ufacting and Marketing）。随着在此直接II阶段的成功完成，下一步的posal包括预定会议，获得IND/IRB临床场地批准，然后是第一阶段人类内临床安全试验。实现这些目标将导致第一个护理水平治疗基于抗纤维化胶原胶质的基本和异常积累的肩部节肢动物以持续和受控的方式为疾病部位提供治疗的组织。