Bifunctional potassium-ATP channel opener and redox catalyst for therapy of spina

用于脊柱治疗的双功能钾-ATP 通道开放剂和氧化还原催化剂

• 批准号: 8769880
• 负责人: PRAKASH G JAGTAP
• 金额: $ 23.15万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769880
• 关键词: A Mouse; Acetylcysteine; Action Potentials; Acute; Adult; Adverse effects; Animal Model; Animals; Antioxidants; Arrhythmia; Ascorbic Acid; Blinded; Cardiac; Chemicals; Chemistry; Clinic; Clinical; Collaborations; Control Groups; Contusions; Development; Diazoxide; Disease; Dose; Drug Exposure; Drug Targeting; Exhibits; Female; Foundations; Heart; Hemorrhagic Shock; Histologic; Hydrogen Peroxide; Hydroxyl Radical; Hyperglycemia; Hypotension; Injury; Investigation; Ischemic Preconditioning; Kidney; Kinetics; Label; Laminectomy; Limb structure; Lung; Marketing; Measures; Medical; Mitochondria; Modeling; Motor; Mus; Neurological outcome; Ohio; Operative Surgical Procedures; Orphan Drugs; Outcome; Oxidation-Reduction; Pathogenesis; Pathologic; Pathway interactions; Penetration; Peroxonitrite; Pharmaceutical Preparations; Phase; Pilot Projects; Pinacidil; Placebo Control; Plasma; Poly(ADP-ribose) Polymerases; Potassium; Pre-Clinical Model; Prevention; Product R; Pyrrolidines; Randomized; Reaction; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Rodent; Rodent Model; Secondary to; Series; Small Business Innovation Research Grant; Solutions; Spin Trapping; Spinal; Spinal Cord; Spinal cord injury; Stress; Superoxides; Testing; Therapeutic; Therapeutic Agents; Tissues; Tocopherols; Toxic effect; Trauma; Universities; Ventricular Fibrillation; antioxidant therapy; attenuation; base; catalase; catalyst; clinical practice; clinically relevant; drinking water; functional outcomes; improved; indexing; innovation; mimetics; novel; pre-clinical; professor; prospective; public health relevance; pyrrolidine; response; small molecule

DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a first-in-class cytoprotective small molecule (R-801) for the prevention of spinal cord injury (SCI) based upon the chemical fusion of 2 discrete chemical domains that: 1) target redox stress via a nitroxide spin-trap moiety, and 2) trigger the endogenous ischemic-preconditioning response via mitochondrial-selective K+-ATP channel activation. We have confirmed a powerful effect of R- 801 in rodent models of trauma, including hemorrhagic shock and ischemia reperfusion injury of the heart, lung, limb, and kidney. In a pilot study of spinal cord trauma (SCT), resuscitation of mice with R-801 produced an accelerating and non-plateauing improvement in motor function (20% total recovery over the first 10 days). R-801 has shown no evidence of toxicity in rodents and large animals. At present, R-801 is the first and only safe, effective, and selective mito-K+-ATP channel opener in development, as no other firm or academic center has succeeded to date in inventing a safe, effective, and selective mito-K+-ATP channel opener. We now propose to verify the pre-clinical feasibility of R-801 in a classic model of SCT and to deepen the understanding of its mechanism of action. Phase 1 SBIR Specific Aim: Establish the PD profile of R-801 in an experimental murine model of SCI. In order to test the hypothesis that R-801 effectively resuscitates SCT, RTX will carry out a pathologic and functional analysis in a prospective, randomized, single-blinded, placebo-controlled investigation in mice. In collaboration with Professor Philip Popovich (Ohio University), adult female CD1 mice will be subjected to SCT using a standardized model of contusion injury. Sham injury (laminectomy without SCT) and vehicle control groups will be compared to a group receiving R-801. The initial 2 doses of R-801 (80 mg/kg/dose), given 1 and 3 h after SCT, will be administered intraperitoneally (IP) in order to obtain a rapid tissue penetration of high levels of the drug int spinal cord tissue. Thereafter, R-801 will be provided in the drinking water (as a 0.2% solution) in order to optimize steady-state drug exposure. In Series A, mice (n=10 per group) will be sacrificed 48 h after SCT for histologic and immunohistochemical analysis of the spinal cord for evidence of of poly(ADP-ribose) polymerase activation and ONOO- formation. In Series B, open field locomotor function will be analyzed in adult female SCI mice (n=10 per group) for a period of 2 months post SCT. Mice will be acclimated to the open field ~1 week prior to SCT. Indices of functional recovery will be measured using the Open field-testing (Basso Mouse Scale; BMS) locomotor rating scale. BMS scores will then be obtained pre-injury and again at weekly intervals. Terminal plasma concentrations of R-801 will be obtained, in order to construct a PD profile relating the efficacy in each dose group to functional, morphologic, and immunohistochemical endpoints. Verification that R-801 resuscitation ameliorates morphologic and functional outcomes will provide a logical foundation for commercial development of parenteral R-801 as an emergent therapy for acute SCI.

描述（由申请人提供）：Radikal Therapeutics (RTX) 正在开发一种一流的细胞保护小分子 (R-801)，用于预防脊髓损伤 (SCI)，其基于 2 个离散化学域的化学融合： 1) 通过硝基氧自旋陷阱部分靶向氧化还原应激，2) 通过线粒体选择性 K+-ATP 通道激活触发内源性缺血预处理反应。我们已经证实 R-801 在啮齿动物创伤模型中具有强大的作用，包括失血性休克和心脏、肺、四肢和肾脏的缺血再灌注损伤。在脊髓损伤 (SCT) 的一项初步研究中，使用 R-801 对小鼠进行复苏，运动功能得到加速且非稳定的改善（前 10 天内总体恢复 20%）。 R-801 没有显示出对啮齿动物和大型动物有毒性的证据。目前，R-801是第一个也是唯一一个正在开发的安全、有效、选择性mito-K+-ATP通道开放剂，迄今为止还没有其他公司或学术中心成功发明出安全、有效、选择性mito-K+ -ATP通道开放剂。我们现在建议在经典的SCT模型中验证R-801的临床前可行性，并加深对其作用机制的理解。第 1 阶段 SBIR 具体目标：在 SCI 实验性小鼠模型中建立 R-801 的 PD 特征。为了检验 R-801 有效复苏 SCT 的假设，RTX 将在小鼠中进行前瞻性、随机、单盲、安慰剂对照研究的病理和功能分析。与 Philip Popovich 教授（俄亥俄大学）合作，将使用标准化的挫伤模型对成年雌性 CD1 小鼠进行 SCT。假损伤（不进行 SCT 的椎板切除术）和载体对照组将与接受 R-801 的组进行比较。 SCT 后 1 小时和 3 小时给予最初 2 剂 R-801（80 mg/kg/剂），将腹膜内 (IP) 给药，以获得高水平药物在脊髓组织中的快速组织渗透。此后，将在饮用水中提供 R-801（0.2% 溶液），以优化稳态药物暴露。在A系列中，小鼠（每组n=10）将在SCT后48小时被处死，用于脊髓的组织学和免疫组织化学分析，以获得聚（ADP-核糖）聚合酶激活和ONOO-形成的证据。在 B 系列中，将在 SCT 后 2 个月内对成年雌性 SCI 小鼠（每组 n=10）进行开放场运动功能分析。在 SCT 前约 1 周，小鼠将适应开放环境。功能恢复指数将使用开放现场测试（巴索小鼠量表；BMS）运动评定量表来测量。然后将在受伤前和每周一次获得 BMS 评分。将获得 R-801 的最终血浆浓度，以构建将每个剂量组的功效与功能、形态学和免疫组织化学终点相关联的 PD 曲线。验证 R-801 复苏可改善形态和功能结果将为肠外 R-801 作为急性 SCI 紧急治疗的商业开发提供逻辑基础。