Evaluation of IPW-5371, a TGFbRI kinase inhibitor, dosed as a single agent or in combination with G-CSF, as a medical countermeasure against the delayed effects of total body irradiation in mice

IPW-5371（一种 TGFbRI 激酶抑制剂）作为单一药物或与 G-CSF 联合用药作为针对小鼠全身照射延迟效应的医学对策的评估

• 批准号: 9763436
• 负责人: Barry P Hart
• 金额: $ 30万
• 依托单位: INNOVATION PATHWAYS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763436
• 关键词: Acute; Address; Advanced Development; Animal Model; Animals; Bioavailable; Breathing; C57BL/6 Mouse; CSF3 gene; Cardiopulmonary; Cessation of life; Chemicals; Chest; Citrulline; Clinical Trials; Collagen; Control Animal; Dose; Dose-Rate; Drug Kinetics; Evaluation; Event; Exposure to; FDA approved; Fibronectins; Fibrosis; Gene Expression; Heart; Heart Injuries; Histologic; Hour; Human; Injections; Intestines; Ionizing radiation; Kidney; Lead; Lethal Dose 50; Life; Lung; Measurement; Measures; Medical; Modeling; Mus; Oral; Organ; Pathway interactions; Pegfilgrastim; Pharmaceutical Preparations; Plasma; Play; Population; Property; Radiation; Radiation exposure; Role; Saline; Signal Transduction; Structure; Temperature; Transforming Growth Factor beta; Whole-Body Irradiation; body system; connective tissue growth factor; disability; effective therapy; experimental study; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; medical countermeasure; mouse model; novel; prevent; radiation countermeasure; radiation effect; radiological attack; secondary endpoint; small molecule; small molecule inhibitor; small molecule therapeutics

Abstract Ionizing radiation (IR) exposure has deleterious effects on multiple organ systems and can be lethal both acutely and later due to the delayed effects. In the event of a deliberate radiation attack or accidental exposure to radiation, a countermeasure can be used to treat exposed populations and prevent death and disability. No agent has been approved by the FDA to treat the delayed effects of acute radiation exposure (DEARE) and our project will address that unmet medical need. IPW-5371 has the properties of an ideal radiation countermeasure: chemically stable at room temperature; orally bio-available; efficacy with once-a-day dosing; targeting a mechanism of action that has been safely inhibited in human clinical trials. The results from the experiments in this proposal will advance the development of IPW-5371 to protect the organs in the case of an unexpected exposure to radiation. We have previously demonstrated that the Innovation Pathways’ small molecule TGF inhibitor, IPW-5371, is effective against DEARE in a thoracic radiation mouse model as measured by improved survival and cardiopulmonary function, when dosed 24 hours post IR. In this proposal, we will establish that IPW-5371 is effective in treating multi- organ DEARE to the heart, lung, kidney and intestine, in a mouse radiation model as a single agent or in combination with G-CSF. Specific Aim 1a: Demonstrate that IPW-5371, as a single agent, can extend survival of C57BL/6 mice exposed to TBI (8.5 Gy) when drug dosing (30mpk/day in chow) is initiated 24 hours post-TBI and continued for 21 months. Specific aim 1b: Demonstrate that IPW-5371, as a single agent can improve secondary endpoints including: decrease fibrosis; protect function; and block TGF signaling in multiple organs of C57BL/6 mice when measured at 4, 9, and 21 months post TBI, following an established mouse model. Specific Aim 2: Establish that IPW-5371 + G-CSF (IPW-5371: 30 mpk per day in chow for 21 months and the G-CSF will be injected for two weeks dosing initiated 24 hours post TBI, 8.5 Gy) can protect against heart, lung, intestine and kidney DEARE (as described in Specific aim 1b) and protect against the early, lethal effects of H-ARS as measured by survival at 30 days verses TBI, untreated mice. There will be a total of 400 mice divided into eight groups. Groups A-D are the un- irradiated controls with Grp A receiving vehicle (SC saline injection for 16 days) Grp B receiving G-CSF, and Grp C receiving IPW-5371, and Grp D receiving IPW-5371+G-CSF. All animals receive drug(s) or vehicle starting 24 hours post TBI. IPW-5371 (administered in chow, 30mpk/day/mouse) for 21 months and G-CSF is administered daily for 16 days (SC, 125 μg/kg (2.5 μg/mouse, qd). Groups E-H receive TBI, 8.5 Gy. Mice to be exposed to uniform TBI at a dose rate of 1.00 Gy per minute. Grp E receives vehicle, Grp F receives G-CSF and Grp G receives IPW-5371 and Grp H receives IPW-5371+G-CSF.

抽象的 电离辐射 (IR) 暴露会对多个器官系统产生有害影响，并且可能致命 由于延迟效应，急性和较晚。如果发生故意或意外的辐射攻击 暴露于辐射后，可以采取对策来治疗暴露人群并预防死亡和 残疾。 FDA 尚未批准任何药物可以治疗急性辐射暴露的延迟效应 （DEARE）和我们的项目将解决未满足的医疗需求。 IPW-5371 具有理想的特性 辐射对策：常温下化学稳定；口服生物利用度；功效与 每日一次给药；针对在人体临床试验中已被安全抑制的作用机制。 本提案中的实验结果将推动 IPW-5371 的开发，以保护 器官意外暴露于辐射的情况下。我们之前已经证明了 Innovation Pathways 的小分子 TGF 抑制剂 IPW-5371 可有效对抗 DEARE 通过改善存活率和心肺功能来测量胸部放射小鼠模型，当 IR后24小时给药。在本提案中，我们将确定 IPW-5371 可有效治疗多发性硬化症 心脏、肺、肾和肠所喜爱的器官，在小鼠辐射模型中作为单一药物或在 与 G-CSF 组合。具体目标 1a：证明 IPW-5371 作为单一代理可以扩展 当开始给药（饲料中 30mpk/天）时，暴露于 TBI（8.5 Gy）的 C57BL/6 小鼠的存活率 24 TBI 后数小时，持续 21 个月。具体目标 1b：证明 IPW-5371 作为单一 药物可以改善次要终点，包括：减少纤维化；保护功能；并阻断 TGF TBI 后 4、9 和 21 个月测量 C57BL/6 小鼠多个器官中的信号传导，如下 已建立的小鼠模型。具体目标 2：确定 IPW-5371 + G-CSF（IPW-5371：30 mpk/ 21 个月的一天内，G-CSF 将注射两周，给药后 24 小时开始 TBI，8.5 Gy）可以保护心脏、肺、肠和肾 DEARE（如具体目标中所述） 1b) 并防止 H-ARS 的早期致命影响（通过 30 天存活率与 TBI 相比来衡量）， 未经治疗的小鼠。总共有 400 只小鼠，分为八组。 A-D 组是非 用 Grp A 接收媒介照射对照（SC 盐水注射 16 天） Grp B 接受 G-CSF， 组C接收IPW-5371，组D接收IPW-5371+G-CSF。所有动物均接受药物或 TBI 后 24 小时车辆启动。 IPW-5371（在食物中给药，30mpk/天/小鼠）持续 21 个月 G-CSF 每天施用，持续 16 天（SC，125 μg/kg（2.5 μg/小鼠，每日一次）。E-H 组接受 创伤性脑损伤 (TBI)，8.5 戈瑞。小鼠以每分钟 1.00 Gy 的剂量率接受均匀的 TBI。 E组接收 车辆，F组接收G-CSF，G组接收IPW-5371，H组接收IPW-5371+G-CSF。