Development of a Bioengineered Heparin from a Non-Animal Source

描述（由申请人提供）：开发非动物来源的生物工程肝素是为了应对2008年初发生的健康危机。这场危机涉及在中国从猪生产的肝素中引入过硫酸软骨素，导致近100名美国人死亡。我们实验室最近的研究表明，现在可以使用发酵结合化学酶法从非动物来源制备生物工程肝素。拟议的5年项目是一项转化和多学科研究工作，涉及伦斯勒理工学院、北卡罗来纳州大学和奥尔巴尼药学院，旨在生产千克数量的非动物源生物工程肝素。通过控制工艺步骤，将制备具有与从动物制备的药用肝素相同结构的生物工程肝素。化学和生物等效性研究将提供必要的临床前数据，以将生物工程肝素作为仿制肝素向前推进。这项为期5年的转化生物工程研究项目的结果将是合成1千克非动物来源的肝素，这是一种明确定义的可交付物，在化学和生物学上与USP肝素等效。第二个明确定义的可交付成果将是一种优化且具有成本效益的工艺，最终可用于生产生物工程化非动物肝素，其规模足以满足美国的治疗需求。这种材料和伴随的过程将提供给有兴趣将这种生物工程肝素作为动物来源肝素的新型和更安全的替代品进入人体临床试验的大小企业合作伙伴。我们假设在良好控制的过程中应用重组表达的生物合成酶可以提供生物工程肝素，其是USP肝素的通用等效物。此外，我们设想这种生物工程肝素对患者更安全，并且可以以与从动物组织获得的肝素竞争的成本制备。这项建议有四个具体目标。1.优化生物工程肝素的生产工艺; 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;和4.扩大规模并生产一公斤生物工程肝素，同时保持化学和生物等效性。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，该生物工程肝素在化学和生物学上与目前从猪肠制备的药物肝素等同。这一过程将提高肝素的安全性和均匀性，并防止这种每天在美国给数十万患者服用的重要药物未来受到污染或掺假。

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.