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

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.