SUMMARY:
UCLA researchers in the School of Medicine and California NanoSystems Institute have developed a novel treatment method utilizing intravenously-delivered nanoparticles loaded with epitopes that interfere with the anaphylaxis response for sustained tolerance to food allergens.
BACKGROUND:
The U.S. Food and Drug Administration (FDA) defines food allergies as an immune system reaction to certain compounds in food. This reaction can manifest into a wide variety of symptoms ranging from mild to life-threatening anaphylaxis that can cause fatal respiratory problems and shock. Today, approximately one in ten children and adults have food allergies, and of those, one-third can lead to life-threatening reactions. There is no cure for food allergies and the most effective management strategy presently is identifying and avoiding the allergenic source(s). Management options after a food allergy has been triggered include antihistamines and EpiPen injections. While oral immunotherapy has been approved by the FDA for the treatment of peanut allergy, all of these management options lack long-term tolerance and require laborious daily maintenance. Development of new therapies with sustained tolerance could ease the high economic cost – estimated to be $24.8 billion in the U.S. – of food allergies.
INNOVATION:
Researchers at UCLA led by Dr. Andre Nel in the School of Medicine have developed a novel approach for inducing systemic tolerance against food allergens. The researchers formulated PLGA nanoparticles (NPs) decorated with liver sinusoidal endothelial cell (LSEC) targeting peptides. They observed that LSECs take up the NPs by an endocytic route, leading to the presentation of their allergenic cargo to regulatory T cells, which serve as a potent source of allergen specific immune suppression. The UCLA researchers injected their NPs into mouse models, and saw that the loaded epitopes designed with high MHC-II binding to peanut allergens such as Ara h2, successfully protected from the development of allergic inflammation and anaphylactic responses. Recently, this technology was upgraded by designing mRNA constructs that encode for a single or combination of Ara h2 epitopes, which could be successfully encapsulated in cationic lipid nanoparticles to target liver endothelial cells for tolerance induction, demonstrated similar efficacy as peptide nanoparticles. This mRNA vaccination strategy holds the advantage of including multiple epitope combinations, which is much easier to achieve than attempting to load peptides with different solubility. The technology is also potentially cheaper and more scalable, with the promise to allow the combination of epitopes from multiple food allergens that can be combined in one vaccine. Together, a safe method for generating long-term tolerogenic effects for allergic reactions could provide much-needed relief and treatment for the large population of children and adult that face daily challenges in avoiding food allergens.
POTENTIAL APPLICATIONS:
• Prevention of anaphylaxis for food allergies, including mixed food allergies
• Treatment of autoimmune diseases such as lupus, rheumatoid arthritis, and type I diabetes using liver sinusoidal endothelial cells to induce antigen-specific immune tolerance
ADVANTAGES:
• Nanoparticles can be intravenously delivered by prophylactic as well as therapeutic administration
• PLGA is FDA-approved, biocompatible, and biodegradable
• Cationic LPN is FDA approved, biocompatible and biodegradable (e.g., COVID mRNA vaccination)
• NP platform is scalable and adaptable, allowing tuning of particle release characteristics and co-encapsulation of synergistic drug combinations and therapies that strengthen Treg generation
DEVELOPMENT-TO-DATE:
The UCLA researchers have demonstrated in vivo efficacy of their treatment method in murine models. It is currently in pre-clinical development.
Related Papers (from the inventors only):
Liu, Q., Wang, X., Liu, X., Kumar, S., Gochman, G., Ji, Y., Lia, Y.P., Chang, C.H., Situ, W., Lu, J., Jiang, J., Mei, K.M., Meng, H. Xia, T., Nel, A.E. Use of Polymeric Nanoparticle Platform Targeting the Liver to Induce Treg-Mediated Antigen-Specific Immune Tolerance in a Pulmonary Allergen Sensitization Model. ACS Nano. 2019, 13(4). 4778-4794.
Liu, Q., Wang, X., Liu, X., Liao, Y.P., Chang, C.H., Mei, K.C., Jiang, J., Tseng, S., Gochman, G., Huang, M., Thatcher, Z., Li, J., Allen, S.D., Lucido, L., Xia, T., Nel, A.E. Antigen-and Epitope-Delivering nanoparticles Targeting Liver Induce Comparable Immunotolerance in Allergic Airway Disease and Anaphylaxis as nanoparticle-Delivering Pharmaceuticals. ACS Nano. 2021, 15(1). 1608-1626.
Liu Q, Wang X, Liao YP, Chang CH, Lia J, Xia T, Nel AE*. Use of a liver-targeting nanoparticle platform to intervene in peanut- induced anaphylaxis through delivery of an Ara h2 T-cell epitope. Nano Today, 2022; 42: 101370.
Xu X, Wang X, Liao YP, Lijia Luo L, Xia T, Nel AE Use of a Liver-Targeting Immune-Tolerogenic mRNA Lipid Nanoparticle Platform to Treat Peanut-induced Anaphylaxis by Single and Multi-epitope Nucleoside Sequence Delivery. ACS Nano, 2023. In Press.