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

摘要 电离辐射(IR)暴露对多个器官系统有有害影响，可能是致命的 由于延迟效应，严重的和后来的。如果发生故意的辐射攻击或意外事故 暴露在辐射中，可以使用对策来治疗暴露人群，防止死亡和 残疾。FDA还没有批准任何药物来治疗急性辐射暴露的延迟效应 (Deare)，我们的项目将解决这一未得到满足的医疗需求。IPW-5371具有理想的特性 辐射对策：在室温下化学稳定；口服生物可用；有效 一天一次给药；针对的是在人体临床试验中被安全抑制的作用机制。 本方案的实验结果将对IPW-5371保护装置的开发起到推动作用 器官在意外暴露于辐射的情况下。我们之前已经证明了 创新路径公司的小分子转化生长因子抑制剂IPW-5371有效地对抗DEARE 胸部放射小鼠模型，通过改善存活率和心肺功能来衡量，当 IR后24小时给药。在这项提案中，我们将确定IPW-5371在治疗多发性硬化症方面是有效的。 器官对心、肺、肾和肠的损害，在小鼠辐射模型中作为单一因素或在 联合应用G-CSF。具体目标1a：证明IPW-5371作为单一制剂可以扩展 剂量为30mpk/d的剂量(30mpk/d)照射C57BL/6小鼠24小时后的存活 伤后数小时，持续21个月。具体目标1b：将IPW-5371作为一个 制剂可改善继发性终点，包括：减少纤维化；保护功能；阻断转化生长因子 脑损伤后4、9、21个月C57BL/6小鼠多器官信号传导 已建立的小鼠模型。具体目标2：建立IPW-5371 G-CSF(IPW-5371：30MPK PER 每天喂养21个月，在24小时后开始注射G-CSF，为期两周 TBI，8.5Gy.)可以预防心、肺、肠和肾的死亡(如特定目的中所述 1b)并防止H-ARS的早期致命影响，通过30天的存活率与TBI的比较来衡量， 未经处理的小鼠。总共将有400只老鼠分成8组。A-D组是联合国 A组接受照射的对照组(SC生理盐水注射16天)B组接受G-CSF， C组接受IPW-5371，D组接受IPW-5371 G-CSF。所有动物都接受药物治疗(S)或 车辆在TBI后24小时启动。IPW-5371(口服，30mpk/天/鼠)21个月 连续16天(SC，125μg/kg(2.5μg/只，qd))。E-H组接收 全身照射，8.5Gy.小鼠接受均匀的全身照射，剂量率为每分钟1.00Gy.GRP E接收 载体，组F接受G-CSF，组G接受IPW-5371，组H接受IPW-5371 G-CSF。

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.