SBIR Phase I: Novel partial cellular reprogramming method for the production of ex vivo blood

这个小企业创新研究（SBIR）一期项目将开发先进的方法，暂时重编程造血干细胞（hsc），使体外生产的血液数量适合输血。将使用一种无转染的方法，可以很容易地转化为临床应用。在美国，每两秒钟就有一个人需要血液，每天需要超过38,000次献血。为了使体外造血在临床上具有相关性，扩增细胞培养必须能够在单位血液中产生2.5x1012个细胞的范围内产生红细胞。要达到这个数量的细胞存在一个根本的障碍。CD34+（造血干细胞）和红系祖细胞通常只能进行短期或有限的体外扩增。该项目的主要目标是对CD34+(hsc)进行重编程，从而激活细胞机制以迫使细胞增殖。尽管来自世界各地的研究努力，在培养中达到临床显著数量的血液以前是不可能的。目标是生产临床相关数量的血液，并在治疗贫血患者和血库行业的临床实践范例中创造转变。建议的活动有何更广泛的影响？如果成功，该项目的更广泛影响/商业潜力将是创造一种可行的替代同种异体输血的方法，并与传统血库和重组红细胞生成素（EPO）的使用竞争。我们期望这项技术的成功发展将对输血的安全性和可获得性以及减少溶血性输血反应产生重大的社会影响。尽管输血的安全性已显著改善，但感染艾滋病毒（1:1. 18万）或丙型肝炎（1:1. 100万）的概率仍非为零。这项工作有望显著提高对体外血液生产的科学和技术理解，并为转化为临床医学提供途径。该项目将对200亿美元的全球输血市场以及价值约530亿美元的EPO市场产生重大影响。

This Small Business Innovation Research (SBIR) Phase I project will develop advanced methods to temporarily reprogram hematopoietic stem cells (HSCs) that will enable ex vivo production of blood in quantities suitable for transfusion. A transfection-free method will be used that can be easily translated into clinical use. Every two seconds someone in the U.S. needs blood and more than 38,000 blood donations are needed every day. In order for ex vivo blood production to be clinically relevant, the expansion cell culture must be able to produce red blood cells in the range contained in a unit of blood: 2.5x1012cells. There exists a fundamental obstacle in reaching this number of cells. CD34+(HSCs) and erythroid progenitors are typically only capable of short-term, or restricted ex vivo expansion. The main objective of this project is to reprogram CD34+(HSCs) such that cellular mechanisms are activated to force cellular proliferation. Despite research efforts from around the world, reaching clinical significant quantities of blood in culture has not been previously possible. The goal is to produce clinically relevant quantities of blood and create a shift in clinical practice paradigms for the treatment of the anemic patient as well as the blood banking industry.What are the broader impacts of the proposed activity?The broader impact/commercial potential of this project, if successful, will be to create a viable alternative to allogenic blood transfusion, and compete with traditional blood banking and the use of recombinant erythropoietin (EPO). We expect that successful development of this technique will have a high societal impact on safety and availability of blood for transfusions as well as a reduction in hemolytic transfusion reactions. Although the safety of transfusions has improved markedly there is still a non-zero probability of getting HIV (1:1.8 Million), or Hepatitis C (1:1 Million). This work is expected to significantly enhance the scientific and technological understanding of ex vivo production of blood and provide a pathway to translation into clinical medicine. This project will have a significant impact in the $20 billion global blood transfusion market, as well as the EPO market, which is valued at about $53 Billion.