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

基本信息

  • 批准号:
    8769880
  • 负责人:
  • 金额:
    $ 23.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 Treeutics(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),其基础是两个离散的化学结构域的化学融合:1)通过氮氧化物自旋陷阱部分靶向氧化还原应激,以及2)通过线粒体选择性K+-ATP通道激活触发内源性缺血预适应反应。我们已经证实了R-801在啮齿动物创伤模型中的强大作用,包括失血性休克和心、肺、四肢和肾脏的缺血再灌注损伤。在一项脊髓损伤(SCT)的先导性研究中,R-801复苏小鼠的运动功能出现了加速和停滞的改善(前10天总恢复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、有效和选择性的mito-K+-ATP通道开放剂,因为到目前为止还没有其他公司或学术中心成功地发明了安全、有效和选择性的mito-K+-ATP通道开放剂。我们现在建议在SCT的经典模型中验证R-801的临床前可行性,并加深对其作用机制的理解。第一阶段SBIR的特定目标:在实验性小鼠脊髓损伤模型中建立R-801的PD谱。为了验证R-801有效复苏SCT的假设,RTX将在小鼠身上进行前瞻性、随机、单盲、安慰剂对照研究的病理和功能分析。在与俄亥俄大学教授菲利普·波波维奇的合作下,成年雌性CD1小鼠将使用标准化的挫伤模型进行SCT。假损伤(没有SCT的椎板切除)和车辆对照组将与接受R-801的组进行比较。SCT后1小时和3小时分别给予R-801(80 mg/kg/剂量)的最初2剂,将通过腹腔给药(Ip),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(作为0.2%的溶液),以优化稳态药物暴露。A组小鼠(每组10只)在SCT后48小时处死动物,进行脊髓组织学和免疫组织化学分析,以确定脊髓内是否存在聚腺苷二磷酸核糖聚合酶的激活和ONOO的形成。在B系列中,将分析SCT后2个月内成年雌性SCI小鼠(每组10只)的旷场运动功能。小鼠在接受SCT前1周进行野外习服。功能恢复指数将使用开放现场测试(Basso Mouse Scale;BMS)运动评级量表进行测量。然后BMS评分将在受伤前获得,并每周一次。将获得R-801的终末血药浓度,以建立PD曲线,将每个剂量组的疗效与功能、形态和免疫组织化学终点联系起来。证实R-801复苏改善了形态和功能结果,这将为R-801作为急性脊髓损伤的紧急治疗方法的商业开发提供逻辑基础。

项目成果

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PRAKASH G JAGTAP其他文献

PRAKASH G JAGTAP的其他文献

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{{ truncateString('PRAKASH G JAGTAP', 18)}}的其他基金

A pro-resolution lipid mediator for treatment of rheumatoid arthritis
用于治疗类风湿性关节炎的促消退脂质介质
  • 批准号:
    9341073
  • 财政年份:
    2016
  • 资助金额:
    $ 23.15万
  • 项目类别:
Hybrid Katp Channel Opener and Redox Catalyst for Lung Transplantation
用于肺移植的混合 Katp 通道开放剂和氧化还原催化剂
  • 批准号:
    8451621
  • 财政年份:
    2013
  • 资助金额:
    $ 23.15万
  • 项目类别:
A Novel Thioredoxin Mimetic Prodrug for Prevention of Bronchopulmonary Dysplasia
一种用于预防支气管肺发育不良的新型硫氧还蛋白模拟前药
  • 批准号:
    8586510
  • 财政年份:
    2013
  • 资助金额:
    $ 23.15万
  • 项目类别:
PARP Inhibitor and Redox Catalyst for Ventilatory Trauma
用于通气创伤的 PARP 抑制剂和氧化还原催化剂
  • 批准号:
    8517334
  • 财政年份:
    2013
  • 资助金额:
    $ 23.15万
  • 项目类别:
Novel Means to Establish Free Radical Balance in the Neonatal Premature Lung
在新生儿早产儿肺中建立自由基平衡的新方法
  • 批准号:
    8124570
  • 财政年份:
    2011
  • 资助金额:
    $ 23.15万
  • 项目类别:
Vasodilating Nitroxide for Therapy of Limb Ischemia-Perfusion Injury
血管舒张一氧化氮治疗肢体缺血灌注损伤
  • 批准号:
    8118720
  • 财政年份:
    2011
  • 资助金额:
    $ 23.15万
  • 项目类别:
Novel antioxidant catalyst for transplant rejection
用于移植排斥的新型抗氧化催化剂
  • 批准号:
    6582431
  • 财政年份:
    2003
  • 资助金额:
    $ 23.15万
  • 项目类别:
PARS inhibitor for cardiac allotransplantation
用于同种异体心脏移植的 PARS 抑制剂
  • 批准号:
    6440952
  • 财政年份:
    2002
  • 资助金额:
    $ 23.15万
  • 项目类别:
PARS inhibitor therapy of smoke inhalation injury
PARS抑制剂治疗烟雾吸入性损伤
  • 批准号:
    6401315
  • 财政年份:
    2001
  • 资助金额:
    $ 23.15万
  • 项目类别:
Novel PARS inhibitor for therapy of colitis
用于治疗结肠炎的新型 PARS 抑制剂
  • 批准号:
    6337327
  • 财政年份:
    1999
  • 资助金额:
    $ 23.15万
  • 项目类别:

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