Engineering Myoblasts for Transplantation

用于移植的工程成肌细胞

• 批准号: 6834140
• 负责人: EDWARD HENRY KISLAUSKIS
• 金额: $ 22.31万
• 依托单位: BIOMEDICAL RESEARCH MODELS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6834140
• 关键词: antisense nucleic acid; apoptosis; biotechnology; cell differentiation; cell growth regulation; developmental genetics; gene expression; genetic manipulation; genetic regulation; inhibitor /antagonist; laboratory mouse; muscle proteins; muscle satellite cell; mutant; myoblasts; newborn animals; protein structure function; stem cell transplantation; technology /technique development

DESCRIPTION (provided by applicant): The primary goals of stem cell biology are to develop practical cell-based tools: 1) to enhance the repair of damaged organs and tissues; and 2) as vehicles for gene therapy to introduce engineered genes to the body to either correct a genetic defect or to provide therapeutic molecules. The use of embryonic stem cells is both controversial and fraught with technical limitations that restrict their current use in a therapeutic setting. In contrast, the use of adult-derived, lineage-specific stem cells is currently the focus of several clinical trials. For example, two clinical trials are under way to assess the value of autologous muscle satellite cell transplantation to improve myocardial function following infarction. Since congestive heart failure accounts for more than 43% of Medicare's annual expenditures, the market for this therapy is substantial. Satellite cells are a resident population of muscle stem cells that can be harvested from virtually any patient with a simple needle biopsy. These cells can be expanded in vitro and then reintroduced in vivo to either repair tissues such as damaged myocardium or skeletal muscle, or instead engineered to express ectopic genes that are of therapeutic value. One of the major hurdles limiting the utility of myoblasts for transplantation is that relatively few of these cells survive past the first few days. We have identified a novel gene that plays a key regulatory role in the myoblast survival and differentiation in mammals. We have also demonstrated that expression of a dominant-negative form of this gene allows myoblasts to survive in the absence of trophic support, thus making it an ideal target for developing cell-based therapies. In this Phase I SBIR project, we will: 1) optimize methods for targeting the function of this protein in primary mouse myoblasts, and 2) determine if these engineered cells survive and contribute to muscle function in vivo.

描述（由申请人提供）：干细胞生物学的主要目标是开发基于细胞的实用工具：1）增强受损器官和组织的修复； 2）作为基因治疗的车辆，将工程基因引入人体以纠正遗传缺陷或提供治疗分子。 胚胎干细胞的使用既有争议，又充满了限制其目前在治疗环境中使用的技术局限性。相反，使用成人谱系特异性干细胞的使用目前是几项临床试验的重点。例如，正在进行两项临床试验，以评估自体肌肉卫星细胞移植的价值，以改善梗塞后心肌功能。由于充血性心力衰竭占Medicare年度支出的43％以上，因此该疗法的市场很大。 卫星细胞是肌肉干细胞的常驻群体，几乎可以从任何简单的针头活检的患者中收获。这些细胞可以在体外扩展，然后在体内重新引入以修复组织，例如损坏的心肌或骨骼肌，或者设计为表达具有治疗价值的异位基因。限制肌细胞对移植的效用的主要障碍之一是，相对较少的细胞在头几天生存。 我们已经确定了一个新的基因，该基因在哺乳动物的成肌细胞存活和分化中起关键的调节作用。我们还证明，该基因的显性阴性形式的表达允许在没有营养支持的情况下生存成肌细胞，从而使其成为开发基于细胞的疗法的理想靶标。在此阶段I SBIR项目中，我们将：1）优化针对原代小鼠成肌细胞中该蛋白质功能的方法，2）确定这些工程细胞是否生存并有助于体内肌肉功能。