Korkmaz, Albright & Sumpter

Peanut allergy is a highly prevalent life-threatening condition among children with no cure. Allergen-specific immunotherapy (ASIT)has emerged as a potentially curative approach for peanut allergy; however, the true potential of ASIT has yet to be achieved due to the concerns of safety, tolerability, cost, and efficacy of prevailing ASIT methods. Specifically, ASIT involves the delivery of the allergen through different routes to reorient abnormal immune mechanisms. Traditional oral and subcutaneous (SC)routes of allergen delivery bear the risk of severe side effects, including anaphylaxis because of systemic allergen exposure. Further, SC delivery suffers from poor patient compliance (less than 5% of the patients choose immunotherapy) due to a large number of painful injections that must be performed over several years. As such, recent efforts have focused on developing safer, more convenient, and clinically-feasible immunotherapies for peanut allergy. Allergen-specific immunotherapy via the cutaneous route has gained much recent attention as an efficient and well-tolerated alternative to the aforementioned ASIT methods, since the skin is readily accessible and highly populated by antigen presenting cells (APCs). In this approach, the fertile immune environment of the skin is strategically targeted to promote tolerance to the allergen, while also minimizing the side effects. Epicutaneous immunotherapy (EPIT) using transdermal patches delivering the allergen to the immune-cell rich skin layers via repeated applications has proven a promising method that improves the condition of peanut allergy patients. Despite these advances, current EPIT methods still result in suboptimal efficiency due to imprecise dosing of the allergen, lengthy patch application times, and empirical targeting without sufficient understanding of skin immune mechanisms and their correlation with the systemic immune responses. Most palpably, poor permeability of the outermost layer of the skin, the stratum corneum, to hydrophilic large molecules (peanut allergens) renders the current EPIT methods inefficient.Moreover, rational cutaneous immunoengineering strategies capitalizing on the recent advances in our understanding of skin immunobiology and in translational biomaterials-based skin-targeted biocargo delivery technologies to specifically manipulate systemic immune responses are scarce.

The goal of this project is to leverage remarkable advances in translational biomaterials, intracutaneous delivery technologies, and our understanding of skin biology and immunology to develop rational approaches to engineering systemic immune responses for the treatment of peanut allergy. Specifically, we propose to gain a fundamental understanding of dissolvable microneedle array (MNA)-based skin-targeted immunomodulation, and apply that understanding to develop safe, efficacious, and clinically viable cutaneous immunoengineering strategies for combating peanut allergy. Over the past decade, we have pioneered the design, fabrication, and functional application of MNAs for in-situengineering of the skin microenvironment. We have shown that we can successfully manufacture MNAs integrating biocargos, and our MNAs can effectively breach the stratum corneum, quickly dissolve (~5 min) in the hydrated skin tissue, and deliver the incorporated single or multiple biocargo(s) to targeted cutaneous microenvironments in both mouse and human skin(Fig.2). Although we and others have extensively used MNAs for intracutaneous vaccination against pathogens, they have yet to be fully investigated for systemic tolerance induction through cutaneous immunomodulation via skin delivery of allergens with or without immune-modifiers. Driven by our expertise with MNAs, biomaterials, skin immunobiology, in vivomouse models, and living human skin explants, we propose to perform mechanistic and translational studies to enable the rational development of MNA-directed immunoengineering methods to combat peanut allergy. Our hypothesis is that in situ MNA-directed immunomodulation with strategically selected tolerogenic compound scan ‘engineer’ the local skin microenvironment to induced urable systemic allergen-specific tolerogenic immune responses. The proposed studies will result in a better understanding of skin immunobiology specifically relevant to the rational development of robust and predictable cutaneous immunoengineering strategies that can safely and efficaciously manipulate systemic adaptive immune responses for the treatment of peanut allergy.