Food allergy (FA), a potentially life-threatening condition, has rapidly increased for 2 decades, affecting 32million Americans with annual costs of $25 billion. Treatment options are extremely limited. Food avoidanceand rescue medication after accidental exposure are primary to FA management. Peanut allergy (PNA) causessevere reactions, often co-existing with tree nut allergies (TNA). Shellfish allergy (ShA) is the main cause ofadult anaphylaxis. Multiple food allergies and cross-reactivity among groups of foods such as tree nuts andshellfish further complicate food avoidance. FA is primarily mediated by abnormally elevated food protein-specific immunoglobulin E (sIgE). The inability to curb persistent food sIgE is a significant barrier to FAtherapeutics. Thus, a non-food restricted treatment working for "all" FA including multiple and severe FAs, withthe ability to reverse elevated sIgE, will narrow treatment gaps and have significant market value.General Nutraceutical Technology LLC (GNT), a NY-based biotechnology startup, is building ongroundbreaking FA research started at Icahn School of Medicine at Mount Sinai. We for the first time isolatedand identified IgE inhibitory compound xanthopurpurin (XPP, a small molecule anthraquinone) from RubiaCordifolia. Our preliminary data show that XPP exhibits favorable bioavailability and is stable with a highpreclinical safety profile (no AEs at 10X daily dose). Strikingly, a 4-week once-a-day oral low dose of XPP(0.4mg /mouse, equivalent to a human adult dose of 0.1g/day based on body surface area44) induced 100%suppression of anaphylaxis, 80-100% of reduction of serum peanut (PN)-sIgE and plasma histamine levels in amurine model of PNA, with no overall immune suppression of IgG or IgA. The preliminary mechanisms ofaction (MOA) include XPP suppressing IgE+ B cells, reducing IL-4 by increased DNA methylation at IL-4promoter, without affecting IL-10 or IFN-γ, and inducing a distinct B cell transcriptomic profile. To ensuremedicinal sourcing sustainability and environmental conservation, we advanced XPP production by generatingsynthetic XPP (sXPP) and its analogs. We found that one of the analogs (named XPP1a) is a superior IgEinhibitor and showed excellent in vitro safety. Therefore, developing an XPP1a product for FA will be thefocus of this STTR phase I grant application. We hypothesize XPPIa will be effective for PNA and for otherFAs such as TNA and ShA, and for severe FAs. Thus, the goal of this 1-year phase I STTR application is togenerate the feasibility of XPP1a efficacy, safety, and PK profile and explore/validate the MOA in conventionaland humanized FA models. We will pursue 2 Specific Aims: Aim # 1: Determine XPP1a protection against IgE-mediated anaphylaxis in conventional and humanized murine models of FA; Aim #2. Determine XPPIa safetyand PK profiles. Completion of this project will lead to the next phase study (Phase II STTR) for IND filingtowards commercialization of XPP1a to treat multiple and severe FA.
Public Health Relevance Statement: Narrative
Food allergy is a serious and major health problem in the US and worldwide for which treatment options are
extremely limited. We identified Xanthopurpurin (XPP a small molecule of anthraquinone) from the plant Rubia
Cordifolia as a possible food allergy treatment because it lowers IgE and completely protects from anaphylaxis.
To ensure medicinal sourcing sustainability and environmental conservation, our company GNT has developed
methods to synthesize XPP and identified a more potent analog XPP1a and we propose to develop XPP1a
product for treating severe and multiple food allergies.
Project Terms: <21+ years old><7S Gamma Globulin> 