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.

摘要 电离辐射（IR）暴露对多个器官系统具有有害影响，并且可以是致命的， 由于延迟效应，急性和晚期。如果发生蓄意的辐射攻击或意外 暴露于辐射，可以使用对策来治疗暴露人群并防止死亡， 残疾。FDA尚未批准任何药物用于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 辐射对策：在室温下化学稳定;口服生物利用度;有效性 每日一次给药;靶向在人体临床试验中已被安全抑制的作用机制。 该方案中的实验结果将促进IPW-5371的开发，以保护 在意外暴露于辐射的情况下对器官造成伤害。我们以前已经证明， Innovation Pathways的小分子TGF β 1抑制剂IPW-5371可有效对抗DEARE， 胸部辐射小鼠模型，通过改善的存活率和心肺功能来测量，当 在本提案中，我们将确定IPW-5371在治疗多发性硬化症中有效。 在小鼠辐射模型中作为单一药剂或在小鼠辐射模型中， 与G-CSF的组合。具体目标1a：证明IPW-5371作为单药可延长 当开始给药（30 mpk/天，在食物中）时暴露于TBI（8.5戈伊）的C57 BL/6小鼠的存活率24 TBI后24小时，并持续21个月。具体目标1b：证明IPW-5371作为单一 药物可改善次要终点，包括：减少纤维化;保护功能;阻断TGF β 1 在TBI后4、9和21个月测量时，C57 BL/6小鼠的多个器官中的信号传导， 一种已建立的小鼠模型。具体目标2：确定IPW-5371 + G-CSF（IPW-5371：30 mpk/ 在21个月内每天在食物中注射G-CSF，并且将在24小时后开始注射G-CSF两周 TBI，8.5戈伊）可保护心脏、肺、肠和肾免于DEARE（如特定目的中所述 1b）并保护免受H-ARS的早期致死作用，如通过30天的存活率相对于TBI所测量的， 未处理的小鼠。将总共400只小鼠分为8组。A-D组为非- 辐照对照组，A组接受溶媒（SC盐水注射16天），B组接受G-CSF， C组接受IPW-5371，D组接受IPW-5371+G-CSF。所有动物接受药物或 车辆在TBI后24小时启动。IPW-5371（在食物中施用，30 mpk/天/小鼠），持续21个月 并且每天施用G-CSF，持续16天（SC，125 μg/kg（2.5 μg/小鼠，qd）。E-H组接收 全身照射，8.5戈伊。将小鼠以每分钟1.00戈伊的剂量率暴露于均匀TBI。E组接收 组F接受G-CSF，组G接受IPW-5371，组H接受IPW-5371+G-CSF。