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; 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，影响了3000万人，1-3造成81％ 4在救援药物和避免后，当前的FA治疗受到限制，没有 长期疗法。通常，产生B细胞和浆细胞的IgE是次群，很少 IgE生产。这些细胞的失调会导致过度的IgE产生，这是一种关键的病理机制 FA过敏性休克。 FA是高度潜水员。花生和树坚果过敏（PNA和TNA）最严重， 很少长大，经常共存。5,6树坚果（TN）之间的交叉反应性进一步增加了反应的风险 使当前的练习复杂化。尽管对食物中过敏原特异性IgE的中心性有数十年的意识 过敏反应，抑制B细胞/血浆IgE的产生仍然是一个主要挑战。 omalizumab，抗 IgE抗体，“陷阱” IgE，但并不靶向生产。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，新颖的疗法应解决广泛的FA 并在停止后口服可持续抑制食物特异性IgE和过敏反应 治疗。 我们首次证明了一个小分子化合物小ber碱（BBR），从 Philodendron皮层，由FA患者抑制外周血单核细胞（PBMC）的IgE产生 在非常低剂量的情况下。14使用BBR使用的真正临床障碍是口服生物利用度较差。15-17我们进一步 开发了一种创新的基于纳米颗粒的公式，名为NIT-X。初步数据显示了口服NIT-X 比具有出色临床前安全性的父级化合物比父母大得多（无敌人 喂食14倍有效的每日剂量后发现的效果），在对PN敏感的小鼠中4周的口服效果 纳米颗粒内2mg bbr的NIT-X（基于身体表面的人剂量为0.3g/天的人剂量 区域18）减少了95-100％PN特异性IgE和100％PN过敏反应，效果持续至少28周 治疗，不影响IgG和IgA水平。 IgE+ B细胞和IgE+浆细胞几乎将 普通的。一个正在进行的实验表明，NIT-X在Cachew（CSH）和胡桃木（WN）过敏中也有效 在鼠模型中补充PN过敏。因此，我们假设NIT-X是非食品限制的 通过恢复正常的IgE调节，治疗干预将对所有FA有效，理论上是有效的。目标 这项为期两年的R21赠款是探索NIT-X作为一种新的疗法，以解决多个FA专注于和 几乎所有TN过敏并探索其机制可能使IgE调节标准化。目标1：确定长期 NIT-X的PN和Multi-TN过敏的IgE介导的过敏反应的定期保护，AIM＃2： 确定导致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调查NIT-X作为安全有效 即使是患有多食物过敏或高反应风险的人的治疗。非食品限制的NIT-X治疗可能 通过恢复IGE调节并提高临床实践来更改FA的过程。