Development of a Bioengineered Heparin from a Non-Animal Source

描述(申请人提供)：从非动物来源开发生物工程肝素是为了应对2008年初发生的一场健康危机。这场危机涉及在中国从猪身上生产的肝素中引入过硫酸软骨素，导致近百名美国人死亡。我们实验室最近的研究表明，利用发酵和化学酶法相结合的方法从非动物来源制备生物工程肝素现在是可能的。拟议的为期5年的项目是一项翻译和多学科研究工作，涉及伦斯勒理工学院、北卡罗来纳大学和奥尔巴尼药学院，旨在生产公斤数量的非动物来源生物工程肝素。通过控制工艺步骤，这种生物工程肝素的结构将与从动物制备的药用肝素完全相同。化学和生物等效性研究将提供必要的临床前数据，以推动生物工程肝素作为仿制肝素的发展。这个为期5年的转化型生物工程研究项目的结果将是合成1公斤非动物来源的肝素，这是一种定义明确的可交付物，在化学和生物上与USP肝素相当。第二种定义明确的可交付物将是一种优化的、具有成本效益的过程，最终可用于生产规模足以满足美国治疗需求的生物工程非动物肝素。有兴趣将这种生物工程肝素作为动物来源肝素的一种新的、更安全的替代品进入人类临床试验的大小企业合作伙伴都将获得这种材料和附带的方法。我们假设，应用重组表达的生物合成酶在良好的控制过程中可以提供一种生物工程肝素，它是USP肝素的仿制等价物。此外，我们预计这种生物工程肝素对患者来说将更安全，并且可以以与从动物组织中获得的肝素竞争的价格制备。这项提议有四个具体目标。1.优化生物工程肝素的生产；2.确认生物工程肝素与USP肝素的化学等效性；3.确认生物工程肝素与USP肝素的生物等效性；4.在保持化学和生物等效性的同时，放大生产1公斤生物工程肝素。公共卫生相关性：拟议的努力通过开发一种制备生物工程肝素的工艺来影响人类健康，这种肝素在化学和生物上与目前从猪肠中制备的药用肝素相当。这一过程将提高肝素的安全性和一致性，并防止这种重要药物未来受到污染或掺假。在美国，每天有数十万患者服用这种重要药物。

DESCRIPTION (provided by applicant): The development of a bioengineered heparin from a non-animal source is in response to a health crisis that took place in early 2008. This crisis involved the introduction of an oversulfated chondroitin sulfate into heparin produced from hogs in China leading to the death of nearly 100 Americans. Recent research in our laboratories suggests that it is now possible to prepare a bioengineered heparin from non-animal sources using fermentation combined with chemoenzymatic methods. The proposed 5-year project is a translational and multi-disciplinary research effort involving the Rensselaer Polytechnic Institute, University of North Carolina and Albany College of Pharmacy, aimed at producing kilogram quantities of non-animal sourced bioengineered heparin. By controlling the process steps this bioengineered heparin will be prepared with a structure identical to the pharmaceutical heparin prepared from animals. Both chemical and bioequivalence studies will provide the necessary pre-clinical data required to carry bioengineered heparin forward as a generic heparin. The results of this 5-year translational bioengineering research project will be the synthesis of 1 kilogram of non-animal sourced heparin, which serves as a well defined deliverable that is chemically and biologically equivalent to USP heparin. A second well-defined deliverable will be an optimized and cost effective process that can be used ultimately to generate bioengineered, non-animal heparin at scales sufficient to satisfy the therapeutic needs in the US. This material and the accompanying process will be made available to both large and small business partners interested in moving this bioengineered heparin into human clinical trails as a novel and safer replacement for animal sourced heparin. We hypothesize that application of recombinantly-expressed biosynthetic enzymes in a well controlled process can afford a bioengineered heparin that is the generic equivalent of USP heparin. Furthermore, we envision that this bioengineered heparin will be safer for patients and can be prepared at costs competitive to heparin obtained from animal tissues. There are four specific aims of this proposal. 1. Optimize the production of bioengineered heparin; 2. Confirm chemical equivalence of bioengineered heparin with USP heparin; 3. Confirm bioequivalence of bioengineered heparin with USP heparin; and 4. Scale-up and produce a kilogram of bioengineered heparin while maintaining chemical and bioequivalence. PUBLIC HEALTH RELEVANCE: The proposed effort impacts human health by developing a process to prepare a bioengineered heparin that is chemically and biologically equivalent to pharmaceutical heparin currently prepared from pig intestine. This process will improve the safety and uniformity of heparin and prevent future contamination or adulteration of this important drug that is administered to several hundred thousand patients each day in the US.