Development of a Bioengineered Heparin from a Non-Animal Source

开发非动物来源的生物工程肝素

• 批准号: 7904164
• 负责人: Jonathan S. Dordick
• 金额: $ 79.89万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904164
• 关键词: Acetates; American; Animal Sources; Animal Testing; Animals; Anions; Antithrombin III; Area Under Curve; Biochemical; Biomedical Engineering; Bovine Spongiform Encephalopathy; Businesses; Capillary Electrophoresis; Cessation of life; Chemicals; China; Chinese Hamster; Chondroitin Sulfates; Clinical; Clinical Data; Complement; Deacetylase; Development; Drug Kinetics; Engineering; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; European Union; F Factor; Family suidae; Fermentation; Fibroblast Growth Factor; Fluorescence; Future; Gel Chromatography; Generic Drugs; Glucosamine; Glucuronic Acids; Glycosaminoglycans; Head; Health; Heparin; Heparin Cofactor II; High Pressure Liquid Chromatography; High-Molecular-Weight Kininogen; Human; Iduronic Acid; Inorganic Sulfates; Institutes; Institution; Intestines; Intravenous; Ions; Kilogram; Kininogenase; Laboratories; Lasers; Letters; Link; Liquid Chromatography; Low-Molecular-Weight Heparin; Methodology; Methods; Molecular Weight; North Carolina; Ovary; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacopoeias; Pharmacy facility; Phase; Plasminogen; Polyacrylamide Gel Electrophoresis; Postdoctoral Fellow; Prekallikrein; Principal Investigator; Process; Production; Protein C; Protein-Carbohydrate Interaction; Prothrombin time assay; Research; Research Institute; Research Project Grants; Safety; Spectrometry, Mass, Electrospray Ionization; Structure; Surface Plasmon Resonance; Therapeutic; Therapeutic Equivalency; Thrombelastography; Thrombin Time Assay; Thromboplastin; Time; Translational Research; United States; United States Food and Drug Administration; Universities; Unspecified or Sulfate Ion Sulfates; Uridine Diphosphate; Variant; Vascular Endothelial Cell; Weight; animal tissue; bioprocess; college; cost; cost effective; drug development; drug discovery; epimerase; experience; improved; in vitro Bioassay; in vivo; interest; ionization; maltose-binding protein; novel; pre-clinical; prevent; professor; public health relevance; response; scale up; subcutaneous; sulfotransferase; ultraviolet

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.

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用生猪生产的肝素中引入过硫酸化的硫酸软骨素导致近100名美国人死亡。我们实验室的最新研究表明，现在可以利用发酵结合化学酶法从非动物来源制备生物工程肝素。拟议的为期 5 年的项目是一项涉及伦斯勒理工学院、北卡罗来纳大学和奥尔巴尼药学院的转化性多学科研究工作，旨在生产公斤级的非动物源生物工程肝素。通过控制工艺步骤，将制备出与从动物身上制备的药用肝素结构相同的生物工程肝素。化学和生物等效性研究都将提供将生物工程肝素作为通用肝素向前发展所需的必要的临床前数据。这个为期 5 年的转化生物工程研究项目的结果将是合成 1 公斤非动物源性肝素，它是一种明确的交付品，在化学和生物学上与 USP 肝素等效。第二个明确的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的非动物肝素，其规模足以满足美国的治疗需求。这种材料和相关工艺将提供给有兴趣将这种生物工程肝素作为动物源肝素的新颖且更安全的替代品进入人体临床试验的大型和小型商业合作伙伴。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，它是 USP 肝素的通用等效物。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成本进行制备。该提案有四个具体目标。 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. 扩大并生产一公斤生物工程肝素，同时保持化学和生物等效性。公共健康相关性：拟议的工作通过开发一种生物工程肝素的制备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中制备的药用肝素相当。这一过程将提高肝素的安全性和均匀性，并防止这种重要药物未来受到污染或掺假，美国每天有数十万名患者服用这种重要药物。