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（由申请人提供）：本研究的目的是为放射清髓后骨髓中造血干细胞再生的人类疗法建立体内原理证明。血液干细胞最容易受到辐射的影响，也是最致命的。我们已经证明了我们的体外治疗原理。如果成功，该项目的产品将是一种基于蛋白质的药物，可以刺激骨髓细胞的生长并防止暴露于辐射的人死亡。没有药物或治疗方法可以刺激造血干细胞的产生； Epogen 和 G-CSF 仅使现有干细胞库分别向红细胞或白细胞分化。此外，FDA 最近发布了黑框警告，称使用这些药物及相关药物会增加癌症复发的风险。我们的治疗药物是一种新型生长因子，我们发现它是由“幼稚”状态的人类干细胞分泌的，并且是人类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，我们是唯一能够将未经基因修饰的人类干细胞恢复并维持在这种难以捉摸的状态的团队，因此在发现这种生长因子、识别和制造其活性形式以及发现其目标方面具有独特的优势。新的生长因子是 在成人组织中基本上不表达。然而，其目标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。为了解决刺激癌生长的潜在风险，我们还鉴定了一种单克隆抗体，它可以模仿我们的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目标受体。我们的方法是用 7 Gy 照射健康小鼠，这会在第 12-15 天杀死 90% 的未经治疗的小鼠。接受治疗的小鼠将通过腹膜内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，定期进行小鼠实验来测试我们的抗癌工厂。到第 19 天，30% 或更高的存活率表明我们的药物有效。处死后，将分析外周血和骨髓血以确定恢复的程度。理想的是第 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类肿瘤的动物的效果。我们开发的药物将有利于核攻击后的防御策略、HSC体外生长以及开发对骨髓或干细胞无影响的抗癌药物等相关领域。