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）