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Oral Therapy for Hemophilia A

A 型血友病的口服疗法

基本信息

批准号：
8514707
负责人：
HENRY DANIELL
金额：
$ 66.32万
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/8514707
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.

描述（由申请方提供）：目前X连锁出血性疾病血友病的标准治疗是基于重组蛋白的静脉内给药。输注的蛋白质是昂贵的，具有短的半衰期（从而限制治疗效果的持续时间），通常被抗体应答靶向（从而使治疗复杂化/中和，产生免疫毒性，并进一步增加成本）;并且需要重复的静脉内接入，这是痛苦和不方便的。治疗后，20-30%的血友病A患者（因子VIII缺乏）和1.5-3%的血友病B患者（因子IX缺乏）形成针对输注因子的抑制性抗体（“抑制剂”）。抑制物形成代表治疗的严重并发症，并且增加疾病的发病率和死亡率。旁路试剂是可用的，但昂贵，不能常规给予，因为它们构成血栓形成的风险。临床免疫耐受诱导（ITI）方案包括长时间频繁的高剂量因子给药，并且非常昂贵。生物工程已经创造了强大的试剂，用于将蛋白质（或编码蛋白质的核酸）非侵入性和成本有效地口服递送到肠道。在这个生物工程研究伙伴关系的应用，我们建议推进这种方法的治疗和口服耐受诱导。最近，Daniell和Herzog实验室发现，口服生物封装的因子IX（以叶绿体转基因植物叶材料的形式）有效地防止了血友病B小鼠在随后的蛋白质替代疗法中形成抑制性抗体和过敏反应。Leong实验室开发了一种基于包装在壳聚糖纳米颗粒中的质粒载体的血友病口服基因疗法。因此，经口递送至肠上皮可提供在患有血友病的动物中部分恢复止血的治疗（从而提供对自发性出血的预防）和免疫调节（从而在不使用免疫抑制药物的情况下防止有害的免疫应答）。为了建立有效的血友病A口服疗法（这是该疾病的更普遍形式，具有更高的抑制剂形成风险），我们组建了一个跨学科团队，包括植物生物技术，生物工程，免疫学和动物模型。具体而言，我们提出i）确定基于纳米颗粒的口服基因疗法在血友病的鼠模型中校正凝血和抑制针对F.VIII的抗体形成的能力; ii）产生F.VIII叶绿体转基因莴苣用于口服递送和预防/逆转蛋白质替代中的抑制剂形成;以及iii）将口服疗法扩大到犬血友病A。最终，我们打算整合这些方法，以提供一种完全以口服为基础的治疗方案，实现预防出血和防止抑制物形成。这种方法可以很容易地适应其他遗传性蛋白质缺乏症或某些过敏症。