Oral Therapy for Hemophilia A

A 型血友病的口服疗法

基本信息

批准号：
8162675
负责人：
HENRY DANIELL
金额：
$ 71.51万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8162675
关键词：
A Mouse A-factor (Streptomyces)Affect Allergy to peanuts Anaphylaxis Animal Model Animals Antibodies Antibody Formation Biomedical Engineering Biotechnology Birth Bypass Canis familiaris Chitosan Chloroplasts Cholera Toxin Protomer B Clinical Coagulation Process Collaborations Complication Data Disease Dose Edible Plants Factor IX Factor VIII Factor VIIa Funding Mechanisms Future Gut associated lymphoid tissue Half-Life Health Care Costs Hemophilia A Hemophilia B Hemorrhage Hemostatic function Human Hypersensitivity Immune Immune Tolerance Immune response Immunology Inherited Intravenous Intravenous infusion procedures Lettuce - dietary Life Link Methods Modeling Morbidity - disease rate Mus Nature Nephrotic Syndrome Nuclear Nucleic Acids Oral Pain Patients Pharmaceutical Preparations Plant Leaves Plants Plasma Plasmid Cloning Vector Prevention Proinsulin Prophylactic treatment Protein Deficiency Proteins Protocols documentation Publishing Quality of life Reagent Recombinant Proteins Recombinants Recruitment Activity Research Risk Staging System Technology Therapeutic Effect Time Tissues Transgenic Mice Transgenic Organisms Transgenic Plants Treatment Protocols Work base biomedical scientist compare effectiveness cost cost effective enzyme replacement therapy gastrointestinal epithelium gene therapy high risk human disease immunoregulation immunotoxicity improved inhibitor/antagonist innovation interdisciplinary approach intestinal epithelium intravenous administration male mortality nanoparticle novel oral tolerance prevent protein expression research study response scale up standard care therapeutic protein tissue culture treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Current standard treatment of the X-linked bleeding disorder hemophilia is based on intravenous administration of recombinant protein. The infused protein is expensive, has a short half-life (thereby limiting duration of the therapeutic effect), is often targeted by antibody responses (thereby complicating/neutralizing therapy, creating immunotoxicities, and further increasing costs); and repeated intravenous access is required, which is painful and inconvenient. Upon treatment, 20-30% of patients with hemophilia A (factor VIII deficiency) and 1.5-3% of hemophilia B patients (factor IX deficiency) form inhibitory antibodies ("inhibitors") against the infused factor. Inhibitor formation represents a serious complication of treatment and increases morbidity and mortality of the disease. Bypass reagents are available, but are expensive and cannot be routinely given because they pose a thrombotic risk. Clinical immune tolerance induction (ITI) protocols consist of frequent high-dose factor administrations for a long period of time and are very expensive. Bioengineering has created powerful reagents for non-invasive and cost-effective oral delivery of the protein (or a nucleic acid encoding the protein) to the gut. Within this Bioengineering Research Partnership application, we propose to advance this approach for treatment and for oral tolerance induction. Recently, the Daniell and Herzog labs found that oral delivery of bioencapsulated factor IX (in form of chloroplast transgenic plant leaf material) effectively prevented formation of inhibitory antibodies and anaphylactic reactions in subsequent protein replacement therapy in hemophilia B mice. The Leong lab developed an oral gene therapy for hemophilia based on plasmid vectors packaged into chitosan nanoparticles. Thus, oral delivery to the intestinal epithelium can provide both therapy that partially restores hemostasis in animals with hemophilia (thereby providing prophylaxis against spontaneous bleeding) and immune modulation (thereby preventing deleterious immune responses without use of immune suppressive drugs). In order to establish effective oral therapy for hemophilia A (which is the more prevalent form of the disease and has a much higher risk of inhibitor formation), we assembled an interdisciplinary team, encompassing plant biotechnology, bioengineering, immunology, and animal models. Specifically, we propose to i) determine the ability of nanoparticle-based oral gene therapy to correct coagulation and suppress antibody formation to F.VIII in murine models of hemophilia; ii) generate F.VIII chloroplast transgenic lettuce for oral delivery and prevention/reversal of inhibitor formation in protein replacement; and iii) scale up oral therapies to canine hemophilia A. Ultimately, we intend to integrate the approaches to provide an entirely oral-based treatment regimen that accomplished prophylaxis against bleeds and prevents inhibitor formation. This approach could readily be adapted to other inherited protein deficiencies or certain allergies. PUBLIC HEALTH RELEVANCE: This project will develop novel methods for treatment of the inherited bleeding disorder hemophilia and for prevention of detrimental immune responses. The oral delivery technologies utilized here will improve quality of life of patients, reduce the risk of life-threatening bleeds, and reduce health care costs.

描述（由申请人提供）：X连锁出血障碍血友病的当前标准治疗基于重组蛋白的静脉内给药。注入的蛋白质昂贵，半衰期短（从而限制了治疗作用的持续时间），通常是由抗体反应（从而使/中和治疗复杂化，产生免疫毒性和进一步增加的成本）的靶向。并且需要重复的静脉输入，这是痛苦和不便的。治疗后，有20-30％的血友病A（因子VIII缺乏）和1.5-3％的血友病患者（因子IX缺乏）形成了抑制性抗体（“抑制剂”）针对注入因子。抑制剂形成代表了严重的治疗并发症，并增加了疾病的发病率和死亡率。旁路试剂可用，但价格昂贵，不能常规地给出，因为它们构成了血栓形成风险。临床免疫耐受诱导（ITI）方案包括长时间频繁的高剂量因子管理，非常昂贵。生物工程为非侵入性和成本效益的口服递送（或编码蛋白质）到肠道的蛋白质（或编码蛋白质的核酸）创造了强大的试剂。在此生物工程研究合作伙伴应用程序中，我们建议推进这种治疗方法和口服耐受性诱导的方法。最近，Daniell和Herzog实验室发现，生物包容性因子IX（以叶绿体转基因植物叶材料的形式）有效地阻止了在血友病B小鼠中随后的蛋白质替代治疗中抑制性抗体和过敏反应的形成。 Leong Lab基于包装到壳聚糖纳米颗粒中的质粒载体开发了一种口服基因疗法。因此，口服到肠上皮的递送可以提供既可以恢复血友病动物的止血的治疗（从而提供了预防自发出血）和免疫调节（从而防止有害免疫反应而无需使用免疫抑制药物）。为了建立血友病A的有效口服治疗（这是疾病的更为普遍形式，并且具有更高的抑制剂形成风险），我们组建了一个跨学科团队，涵盖了植物生物技术，生物工程学，免疫学，免疫学和动物模型。具体而言，我们建议i）确定基于纳米颗粒的口服基因治疗校正凝血和抑制F.VIII抗体形成的能力； ii）生成F.viii叶绿体转基因生菜，用于口服递送和预防/逆转蛋白质替代的抑制剂； iii）将口服疗法扩展到犬血友病A。最终，我们打算整合提供完全基于口服的治疗方案的方法，该治疗方案可实现针对出血的预防并防止抑制剂形成。这种方法可以很容易地适应其他遗传的蛋白质缺陷或某些过敏。公共卫生相关性：该项目将开发用于治疗遗传性出血性血友病和预防有害免疫反应的新方法。这里使用的口服交付技术将改善患者的生活质量，降低威胁生命的出血风险，并降低医疗保健成本。