Novel therapeutic for hematopoietic stem cell regeneration in bone marrow post my

描述（由申请方提供）：本研究的目的是建立一种用于放射性骨髓消融术后骨髓造血干细胞再生的人体治疗方法的体内原理证明。造血干细胞是最容易受到辐射影响和最致命的。我们已经证明了我们的体外治疗的原理。如果成功的话，这个项目的产品将是一种蛋白质药物，它将刺激骨髓细胞的生长，并防止暴露在辐射下的人死亡。没有药物或治疗可刺激造血干细胞的产生; Epogen和G-CSF仅使现有干细胞池分别向红细胞或白色血细胞分化。此外，FDA最近发布了一个黑匣子警告，使用这些药物和相关药物会增加癌症复发的风险。我们的治疗剂是一种新的生长因子，我们发现它是由“幼稚”状态的人类干细胞分泌的，是人类多能干细胞生长所需的唯一生长因子或细胞因子。到目前为止，我们是唯一一个能够恢复和维持这种难以捉摸的状态的遗传未修饰的人类干细胞的小组，因此我们处于独特的位置来发现这种生长因子，识别和制造其活性形式并发现其目标。该新型生长因子， 在成体组织中基本上不表达。然而，其靶向生长因子受体在骨髓造血干细胞和癌细胞上表达，尽管形式略有不同。为了解决刺激癌细胞生长的潜在风险，我们还鉴定了一种单克隆抗体，它模拟了我们生长因子的刺激功能，但重要的是，它不能识别癌细胞上出现的靶受体。我们的方法是用7-戈伊照射健康小鼠，在第12-15天杀死90%的未治疗小鼠。处理的小鼠将通过ip注射每天一次接受蛋白质生长因子或单克隆抗体。我们有一个动物团队，定期进行小鼠实验，测试我们的抗癌Fab。到第19天，30%或更高的存活率表明我们的药剂有效。处死后，将分析外周血和骨髓血，以确定恢复程度。理想情况是在第19天恢复80%。然后，我们将测试我们的候选治疗性单克隆抗体对携带人肿瘤的动物的作用。我们开发的药物将有利于核攻击后的防御策略，体外HSC生长以及对骨髓或干细胞没有影响的抗癌药物的开发等相关领域。

DESCRIPTION (provided by applicant): The purpose of this study is to establish in vivo proof of principle for a human therapeutic for hematopoietic stem cell regeneration in the bone marrow after myeloablation from radiation. Blood stem cells are the most susceptible to the effects of radiation and the most lethal. We have already demonstrated proof of principle for our therapeutic in vitro. If successful, the product of this project will be a protein-based drug that ill stimulate the growth of bone marrow cells and prevent death in people exposed to radiation. There is no drug or treatment available that stimulates the production of hematopoietic stem cells; Epogen and G-CSF only skew the differentiation of the existing pool of stem cells toward red blood cells or white blood cells, respectively. In addition, the FDA recently issued a Black Box warning that the use of these and related drugs increases risk of cancer recurrence. Our therapeutic is a novel growth factor that we discovered is secreted by "naïve" state human stem cells and is the only growth factor or cytokine required for human pluripotent stem cell growth. To date, we are the only group that has been able to revert and maintain genetically unmodified human stem cells in this elusive state, so were uniquely positioned to discover this growth factor, to identify and make its active form and to discover its target. The novel growth factor is essentially not expressed in adult tissue. However, its target growth factor receptor is expressed on bone marrow hematopoietic stem cells and on cancer cells, albeit in slightly different forms. To address the potential risk of stimulating cancerous growth, we have also identified a monoclonal antibody that mimics the stimulatory function of our growth factor, but importantly does not recognize the target receptor as it appears on cancer cells. Our approach is to irradiate healthy mice to 7- Gy, which kills 90% of untreated mice Day 12-15. Treated mice will receive either the protein growth factor or the monoclonal antibody once daily by ip injection. We have an animal team that routinely performs mouse experiments testing our anti-cancer Fabs. By Day 19, 30% or greater survival indicates effectiveness of our agent. After sacrifice, peripheral and bone marrow blood will be analyzed to determine the extent of recovery that has taken place. Ideal is 80% recovery by Day 19. We will then test the effect of our candidate therapeutic monoclonal antibody on animals bearing human tumors. The drug we develop would benefit related fields of defense strategies following nuclear attack, HSC growth in vitro, and development of anti-cancer drugs that have no effect on bone marrow or stem cells.