A targeted immunomodulator for the treatment of acute sickle crisis

治疗急性镰状危象的靶向免疫调节剂

• 批准号: 8979976
• 负责人: Steven Isaacman
• 金额: $ 22.49万
• 依托单位: NANOMETICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979976
• 关键词: Acute; Address; Affect; Affinity; American; Anti-Inflammatory Agents; Anti-inflammatory; Biotechnology; Chronic; Data; Development; Disease; Dose; Drug Kinetics; Emergency department visit; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Goals; Hereditary Disease; Human; Immunomodulators; Inflammation; Inflammation Mediators; Knowledge; Laboratories; Lead; Leukocytes; Libraries; Medicine; Metabolism; Modeling; Mus; Muscle Form Glycogen Phosphorylase; Oral; Outcome; Oxidative Stress; Pain; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphorylase a; Phosphorylases; Pre-Clinical Model; Production; Property; Recurrence; Recycling; Reporting; Resolution; Sickle Cell Anemia; Small Business Innovation Research Grant; Specificity; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Transgenic Mice; Treatment outcome; United States National Institutes of Health; Vascular Diseases; analog; college; commercial application; design; global health; hemodynamics; improved; inhibitor/antagonist; intraperitoneal; mouse model; novel; pre-clinical; public health relevance; research study; sickling; small molecule; success; technological innovation; venule

 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a global health issue that affects over 13 million people worldwide, including ~100,000 Americans. SCD is a chronic and multifactorial disease, which is characterized by a persistent milieu of oxidative stress, inflammation, and painful episodes of sickle crisis. The Product and Long-Term Goal: Nanometics is developing a targeted small molecule enzyme inhibitor as an acute therapeutic for sickle crisis. It is anticipated that this new immunomodulatory approach will be useful to expedite the time to reach resolution of crisis. The Technological Innovation: The Nanometics approach utilizes a targeted enzyme inhibitor with high specificity and picomolar affinity to block metabolism of an endogenous anti-inflammatory molecule and allow for its accumulation to therapeutically beneficial levels. Phase I Hypotheses: This Phase I SBIR will demonstrate the feasibility of the Nanometics enzyme inhibitor as an oral therapeutic for acute crisis. The hypotheses that will be tested during the Phase I SBIR experiments are that a single oral dose of the inhibitor will be: 1) as effective as a single intraperitoneal dose; and 2) will convey a therapeutic benefit for > 24 h. Specific Aims: Specific Aim 1. Demonstrate the pharmacological and concentration dependent effects of a single oral dose of MTDIA in the microvasculature of BERK mice. Phase II: Phase II SBIR studies will establish the mechanism of action and regulatory toxicity profile. Commercial Application: Each year in the U.S., there are approximately 190,000 emergency room visits by patients seeking treatment for sickle crisis. There is no commercial therapeutic to avert imminent episodes of crisis or to reduce the time to resolution of crisis once it has begun.

 描述（由申请人提供）：镰状细胞病（SCD）是一种全球性健康问题，影响全球1300多万人，其中包括约10万美国人。SCD是一种慢性和多因素疾病，其特征在于持续的氧化应激、炎症和疼痛的镰状危象发作。产品和长期目标：Nanometics正在开发一种有针对性的小分子酶抑制剂，作为镰刀危机的急性治疗剂。预计这种新的免疫调节方法将有助于加快解决危机的时间。技术创新：Nanometics方法利用具有高特异性和皮摩尔亲和力的靶向酶抑制剂来阻断 本发明提供了一种用于抑制内源性抗炎分子的代谢并允许其积累至治疗有益水平的方法。I期假设：本I期SBIR将证明Nanometics酶抑制剂作为急性危象口服治疗剂的可行性。将在I期SBIR实验期间测试的假设是，抑制剂的单次口服剂量将：1）与单次腹膜内剂量一样有效;和2）将传达> 24小时的治疗益处。具体目标：具体目标1。证明BERK小鼠微血管中MTDIA单次口服剂量的药理学和浓度依赖性作用。II期：II期SBIR研究将建立作用机制和调节毒性特征。商业应用：每年在美国，约有190 000名病人到急诊室寻求镰刀危机的治疗。没有商业治疗方法可以避免即将发生的危机，或者减少危机开始后解决危机的时间。