Oral Therapy for Hemophilia A

A 型血友病的口服疗法

• 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
• 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

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）：目前X连锁出血性疾病血友病的标准治疗基于静脉内施用重组蛋白。输注的蛋白质价格昂贵，半衰期短（从而限制了治疗效果的持续时间），通常是抗体反应的目标（从而使治疗复杂化/中和，产生免疫毒性，并进一步增加成本）；且需要反复静脉通路，痛苦且不方便。治疗后，20-30% 的 A 型血友病（因子 VIII 缺乏）患者和 1.5-3% 的 B 型血友病（因子 IX 缺乏）患者会形成针对输注因子的抑制性抗体（“抑制剂”）。抑制剂的形成代表治疗的严重并发症并增加疾病的发病率和死亡率。旁路试剂是可用的，但价格昂贵，并且不能常规使用，因为它们会带来血栓形成的风险。临床免疫耐受诱导（ITI）方案包括长期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，可以将蛋白质（或编码蛋白质的核酸）以非侵入性且经济高效的方式口服递送至肠道。在这项生物工程研究合作伙伴申请中，我们建议推进这种治疗和口服耐受诱导的方法。最近，Daniell 和 Herzog 实验室发现，口服生物封装因子 IX（以叶绿体转基因植物叶子材料的形式）可有效防止血友病 B 小鼠后续蛋白质替代疗法中抑制性抗体的形成和过敏反应。 Leong 实验室开发了一种基于包装到壳聚糖纳米粒子中的质粒载体的血友病口服基因疗法。因此，口服给药至肠上皮可以提供部分恢复血友病动物止血的治疗（从而预防自发性出血）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反应）。为了建立有效的 A 型血友病（一种更常见的疾病形式，形成抑制剂的风险更高）的有效口服疗法，我们组建了一个跨学科团队，涵盖植物生物技术、生物工程、免疫学和动物模型。具体来说，我们建议 i) 确定基于纳米颗粒的口服基因疗法在血友病小鼠模型中纠正凝血和抑制 F.VIII 抗体形成的能力； ii)产生用于口服递送的F.VIII叶绿体转基因生菜并预防/逆转蛋白质替代中抑制剂的形成； iii) 扩大犬血友病 A 的口服治疗。最终，我们打算整合这些方法，提供完全基于口服的治疗方案，实现预防出血并防止抑制剂形成。这种方法可以很容易地适应其他遗传性蛋白质缺陷或某些过敏症。 公共健康相关性：该项目将开发治疗遗传性出血性疾病血友病和预防有害免疫反应的新方法。这里使用的口服给药技术将改善患者的生活质量，降低危及生命的出血风险，并降低医疗费用。