Allergen-specific mRNA-lipid nanoparticle therapy for prevention and treatment of experimental allergy in mice
Allergic diseases have reached epidemic proportions globally, calling attention to the need for better treatment and preventive approaches. Herein, we developed allergen-encoding messenger RNA (mRNA)–lipid nanoparticle (LNP) strategies for both therapy and prevention of allergic responses. Immunization with allergen-encoded mRNA-LNPs modulated T cell differentiation, inhibiting the generation of T helper type 2 and type 17 cells upon allergen exposure in experimental asthma models induced by ovalbumin, and naturally occurring house dust mite (HDM) and the major HDM allergen Der p1. Allergen-specific mRNA-LNP treatment attenuated clinicopathology in both preventive and established allergy models, including reduction in eosinophilia, mucus production, and airway hypersensitivity, while enhancing production of allergen-specific IgG antibodies and maintaining low IgE levels. Additionally, allergen-specific mRNA-LNP vaccines in mice elicited a CD8+CD38+KLRG– T cell response as seen following SARS-CoV-2 mRNA vaccination in humans, underscoring a conserved immune mechanism across species, regardless of the mRNA-encoded protein. Notably, mRNA-LNP vaccination in combination with an mTOR inhibitor reduced the CD8+ T cell response without affecting the vaccine-induced anti-allergic effect in the preventive model of asthma. This technology renders allergen-specific mRNA-LNP therapy a promising approach for prevention and treatment of allergic diseases. Overall design: Mice received 2 doses of empty LNP (LNP) or OVA-mRNA LNP vaccine (mRNA) on days 0 and 7. Everolimus (Ev. or EVL) was administered daily from day -2 to 12 post-vaccination. Mice were OVA + Alum sensitized on days 24 and 36 and subsequently OVA challenged for 4 consecutive days (days 48-51). Lung tissue were collected 2 days after the final challenge (day 53). Naïve mice served as unmanipulated controls.