IgE Suppressing Berberine Nanomedicine for Treatment of Peanut and Tree nut Allergies

抑制 IgE 的小檗碱纳米药物用于治疗花生和坚果过敏

• 批准号: 10649110
• 负责人: Xiu-Min Li
• 金额: $ 26.23万
• 依托单位: GENERAL NUTRACEUTICAL TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649110
• 关键词: Address; Adverse effects; Affect; Aftercare; Allergens; Allergic; Allergy to peanuts; Anaphylaxis; Anti-Allergic Agents; Antibodies; Awareness; B-Lymphocytes; BCL6 gene; Berberine; Binding; Biological Availability; Body Surface Area; C3H/HeJ Mouse; Cashew nut; Cells; Childhood; Clinical; Data; Development; Dose; Early treatment; Food; Food Hypersensitivity; Formulation; Genes; Genetic Transcription; Goals; Grant; Human; Hypersensitivity; IgE; Immunoglobulin A; Immunoglobulin G; Individual; Interferon Type II; Interleukin-13; Interleukin-4; Intervention; Investigation; Juglans; Knowledge; Mediating; Minor; Molecular; Monitor; Mus; Names; Nut Hypersensitivity; Nuts; Oral; Oral Administration; Outcome; Outcome Measure; Parents; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Philodendron; Pilot Projects; Plasma; Plasma Cells; Population; Production; Public Health; Reaction; Regulation; Resistance; Risk; STAT6 gene; Scientific Advances and Accomplishments; Serum; Signal Transduction; Site; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Transcription Repressor; Trees; Work; anti-IgE; chemokine; clinical practice; cross reactivity; curative treatments; cytokine; effective therapy; experience; experimental study; feeding; in vivo; innovation; mouse model; nanomedicine; nanoparticle; novel; novel therapeutics; omalizumab; oral immunotherapy; pre-clinical; preclinical safety; prevent; programs; promoter; reconstitution; response; restoration; restraint; small molecule; transcriptome sequencing

Abstract (30 lines) Food allergy (FA) is a substantial US public health problem, affecting over 30 million people, 1-3 causing 81% of pediatric anaphylaxis. 4 Outside of rescue medication and avoidance, current FA treatment is limited with no long-lasting therapeutics. Normally, IgE producing B cells and plasma cells are minor population with minimal IgE production. Dysregulation of these cells causes excessive IgE production, a key pathological mechanism of FA anaphylactic shock. FA is highly diverse. Peanut and tree nut allergies (PNA and TNA) are most severe, rarely outgrown, and often co-exist.5,6 Cross reactivity among tree nut (TN) further increase the risk of reactions complicate current practice. Despite decades of awareness about the centrality of allergen-specific IgE in food anaphylaxis7, inhibiting IgE production by B cells/plasma remains a major challenge. Omalizumab, the anti- IgE antibody, “traps” IgE but does not target production. Oral immunotherapy (OIT), including Palforzia® for peanut (PN) OIT, may paradoxically increase IgE.8-13 Therefore, novel therapeutics should address broad FA and be orally administered with sustainable suppression of food specific IgE and anaphylaxis after stopping treatment. We, for the first time, demonstrated that a small molecule compound berberine (BBR), isolated from Philodendron cortex, inhibited IgE production by peripheral blood mononuclear cells (PBMC) from FA patients at very low doses.14 real clinical barrier to use of BBR use is poor oral bioavailability.15-17 We further developed an innovative nanoparticle-based formulation, named NIT-X. Preliminary data showed oral NIT-X is significantly more bioavailable than parent compound with an excellent preclinical safety profile (no adverse effects found after feeding 14x effective daily dose), and that in PN-sensitized mice 4-weeks of once-a-day oral NIT-X at 2mg BBR within the nano particle (equivalent to a human dose of 0.3g/day, based on body surface area18) reduced 95-100% PN-specific IgE and 100% PN anaphylaxis with effects lasting at least 28 weeks post treatment, without affecting IgG and IgA levels. IgE+ B cells and IgE+ plasma cells were reduced nearly to normal. An ongoing experiment showed NIT-X also worked in cashew (CSH) and walnut (WN) allergy in addition to PN allergy in murine model. We therefore hypothesize that NIT-X, as non-food restricted therapeutic intervention, will be effective, theoretically, for all FA by restoring normal IgE regulation. The goal of this 2-year R21 grant is to explore NIT-X as a novel therapeutic to resolve multiple FA focusing on and nearly all TN allergy and explore its mechanisms possibly normalize IgE regulation. Aim # 1: Determine long- term protection against IgE-mediated anaphylaxis in PN and multi-TN allergies by NIT-X, and Aim #2: Identify the mechanisms contributing to sustained suppression of IgE production by NIT-X. Successful completion of this proposal would provide a strong rationale to further investigate NIT-X as a safe and effective treatment even for those with multi-food allergies or high reaction risk. Non-food-restricted NIT-X therapy may change the course of FA by restoration of IgE regulation, and advance clinical practice.

摘要（30行） 食物过敏 (FA) 是美国的一个重大公共卫生问题，影响超过 3000 万人，其中 1-3 占 81% 小儿过敏反应。 4 除了救援药物和避免治疗外，目前的 FA 治疗方法有限，没有任何治疗方法。 长效治疗。通常，产生 IgE 的 B 细胞和浆细胞是少数群体，具有极少的数量。 IgE 产生。这些细胞的失调导致 IgE 产生过多，这是一个关键的病理机制 FA 过敏性休克。 FA 高度多样化。花生和坚果过敏（PNA 和 TNA）最为严重， 很少会被淘汰，并且经常共存。5,6 树坚果 (TN) 之间的交叉反应进一步增加了反应风险 使当前的实践变得复杂。尽管几十年来人们认识到食品中过敏原特异性 IgE 的中心地位 过敏反应7，抑制 B 细胞/血浆产生 IgE 仍然是一个主要挑战。奥马珠单抗，抗 IgE 抗体“捕获”IgE，但不靶向产生。口服免疫疗法 (OIT)，包括 Palforzia® 花生 (PN) OIT，可能会矛盾地增加 IgE。8-13 因此，新型疗法应解决广泛的 FA 停药后口服可持续抑制食物特异性 IgE 和过敏反应 治疗。 我们首次证明，小分子化合物小檗碱（BBR）是从 喜林芋皮质，抑制 FA 患者外周血单核细胞 (PBMC) 产生 IgE 非常低的剂量。14 使用 BBR 的真正临床障碍是口服生物利用度差。15-17 我们进一步 开发了一种基于纳米颗粒的创新配方，名为 NIT-X。初步数据显示口服 NIT-X 比母体化合物的生物利用度显着提高，并具有出色的临床前安全性（无不良反应） 喂养 14 倍有效每日剂量后发现的效果），以​​及 PN 致敏小鼠每天口服 4 周的效果 NIT-X 纳米粒子内含有 2mg BBR（相当于人体剂量 0.3g/天，基于体表 区域 18) 减少 95-100% PN 特异性 IgE 和 100% PN 过敏反应，效果至少持续 28 周 治疗，不影响 IgG 和 IgA 水平。 IgE+ B 细胞和 IgE+ 浆细胞几乎减少至 普通的。一项正在进行的实验表明，NIT-X 对腰果 (CSH) 和核桃 (WN) 过敏也有效 除了小鼠模型中的 PN 过敏外。因此，我们假设 NIT-X 作为非食品限制 理论上，通过恢复正常的 IgE 调节，治疗干预对所有 FA 都是有效的。目标 这项为期 2 年的 R21 拨款的其中一部分是探索 NIT-X 作为一种新型疗法来解决多种 FA，重点关注和 几乎所有的TN过敏并探索其可能使IgE调节正常化的机制。目标#1：确定长期 通过 NIT-X 对 PN 和多 TN 过敏中 IgE 介导的过敏反应提供长期保护，目标 #2： 确定 NIT-X 持续抑制 IgE 产生的机制。成功的 该提案的完成将为进一步研究 NIT-X 作为一种安全有效的方法提供强有力的理由 即使对多种食物过敏或反应风险高的人也可以进行治疗。非食物限制的 NIT-X 疗法可能 通过恢复 IgE 调节来改变 FA 的病程，并推进临床实践。