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

摘要（30行） 食物过敏（FA）是美国一个重要的公共卫生问题，影响超过3000万人，1-3造成81%的 小儿过敏症4除了急救药物和避免，目前的FA治疗是有限的，没有 长期治疗。通常，产生IgE的B细胞和浆细胞是少数群体， IgE产生。这些细胞的失调会导致IgE产生过多，这是一种关键的病理机制 FA过敏性休克FA是非常多样化的。花生和树坚果过敏（PNA和TNA）是最严重的， 树坚果（TN）之间的交叉反应进一步增加了反应的风险， 使现行做法复杂化。尽管几十年来人们一直意识到食物中过敏原特异性IgE的中心地位， 过敏7，抑制B细胞/血浆的IgE产生仍然是一个主要的挑战。奥马珠单抗， 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可能矛盾地增加IgE。8 -13因此，新的治疗方法应该解决广泛的FA 口服给药，停药后可持续抑制食物特异性IgE和过敏反应 治疗 我们首次证明了从植物中分离的小分子化合物小檗碱（BBR）， 喜林芋皮层抑制FA患者外周血单个核细胞（PBMC）产生IgE 使用BBR的真实的临床障碍是口服生物利用度差。15 -17我们进一步 开发了一种创新的纳米颗粒配方，名为NIT-X。初步数据显示口服NIT-X 具有优异临床前安全性特征（无不良反应 在喂食14倍有效日剂量后发现的效果），以及在PN致敏小鼠中每天一次口服4周后发现的效果 纳米颗粒内2 mg BBR的NIT-X（基于体表，相当于0.3g/天的人体剂量 面积18）降低95-100% PN特异性IgE和100% PN过敏反应，作用持续至少28周 治疗，而不影响IgG和伊加水平。IgE+ B细胞和IgE+浆细胞几乎减少到 正常一项正在进行的实验表明，NIT-X也在腰果（CSH）和核桃（WN）过敏中起作用。 除了在鼠模型中的PN过敏。因此，我们假设NIT-X作为非食物限制的 理论上，通过恢复正常的IgE调节，治疗性干预对所有FA都有效。目标 这项为期2年的R21赠款的目的是探索NIT-X作为一种新的治疗方法，以解决多种FA， 几乎所有的TN过敏，并探讨其机制可能正常IgE调节。目标1：确定长期 NIT-X在PN和多种TN过敏中对IgE介导的速发型过敏反应的长期保护作用，以及目标#2： 确定NIT-X持续抑制IgE产生的机制。成功 该提案的完成将为进一步研究NIT-X作为一种安全有效的 即使是对多种食物过敏或高反应风险的人也可以接受治疗。非食物限制的NIT-X疗法可能 通过恢复IgE调节改变FA的进程，并推进临床实践。

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.