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

骨髓后造血干细胞再生的新疗法

• 批准号: 8714632
• 负责人: CYNTHIA C. BAMDAD
• 金额: $ 20.95万
• 依托单位: MINERVA BIOTECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714632
• 关键词: Address; Adult; Affect; Am 80; Animals; Antineoplastic Agents; Biometry; Blood; Blood Banks; Blood Cell Count; Blood Cells; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Purging; Bone Marrow Stem Cell; Bone Marrow Transplantation; Boxing; CSF3 gene; Cancerous; Cells; Cessation of life; Control Groups; DU145; Development; Disease; Dose; Effectiveness; Engineering; Engraftment; Epoetin Alfa; Erythrocytes; Exposure to; Goals; Growth; Growth Factor; Growth Factor Receptors; Health; Hematopoietic stem cells; Human; Immune; In Vitro; Injection of therapeutic agent; Left; Leukocytes; Life; Malignant Neoplasms; Mammary Neoplasms; Mediating; Monoclonal Antibodies; Mucin-1 Staining Method; Mus; NME1 gene; Natural regeneration; Nuclear; PC3 cell line; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pluripotent Stem Cells; Positioning Attribute; Production; Prostatic Neoplasms; Proteins; Protocols documentation; Radiation; Reagent; Recovery; Risk; Stem cells; T47D; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Tissues; Transplantation; Work; anti-cancer therapeutic; assault; base; cancer cell; cancer recurrence; cancer risk; cancer stem cell; cancer therapy; cell growth; chemotherapy; cytokine; human stem cells; in vivo; induced pluripotent stem cell; killings; leukemia; mortality; novel; novel therapeutics; prevent; radiation effect; receptor; reconstitution; research study; stem; tumor; tumor growth

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.

描述（由适用提供）：这项研究的目的是在骨髓中骨髓化后的骨髓中造血干细胞再生的人体治疗原理证明。血管细胞最容易受到辐射的影响和最致命的作用。我们已经证明了体外治疗性的原理证明。如果成功的话，该项目的产物将是一种基于蛋白质的药物，可刺激骨髓细胞的生长并防止暴露于辐射的人死亡。没有可刺激造血干细胞产生的药物或治疗方法。 EPOGEN和G-CSF仅分别将干细胞池的分化分别偏分别为红细胞或白细胞。此外，FDA最近发布了一个黑匣子警告，称使用这些药物和相关药物会增加癌症复发的风险。我们的理论是我们发现的一种新颖的生长因子，是由“幼稚”的人类干细胞分泌的，是人多能干细胞生长所需的唯一生长因子或细胞因子。迄今为止，我们是唯一能够在这种难以捉摸的状态下恢复和维持遗传未修饰的人类干细胞的群体，因此在发现这种生长因子的情况下是独特的，以识别和使其活跃形式并发现其目标。新的生长因素是 基本上没有在成人组织中表达。但是，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。为了解决刺激癌性生长的潜在风险，我们还确定了一种模拟我们生长因子的刺激功能的单克隆抗体，但重要的是，当癌细胞上出现的靶心受体并未识别靶受体。我们的方法是将健康的小鼠照射到7-GY，这杀死了12-15天未经治疗的小鼠的90％。治疗的小鼠将每天通过IP注射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通常执行鼠标实验测试我们的抗癌晶圆厂。到第19天，30％或更高的生存表明我们的代理人的有效性。牺牲后，将分析周围和骨髓血液，以确定发生的恢复程度。理想是到第19天的80％恢复。然后，我们将测试候选治疗性单克隆抗体对具有人类肿瘤的动物的影响。我们开发的药物将使核攻击，体外HSC生长以及对骨髓或干细胞没有影响的抗癌药物的发展后，有益于国防策略的相关领域。