DNA replicons for prevention and treatment of allergy

Over the past few decades the prevalence of atopic diseases such as allergic rhinitis, atopic eczema and asthma has substantially increased in the industrialized world. Up to now, the only preventive or even curative approach for treatment of type I allergy is allergen-specific immunotherapy (SIT), which can induce a long-term, antigen- specific, protective immune response resulting in long-lasting alleviation of allergic manifestations. However, the potential side-effects associated with conventional SIT using whole allergen extract limit its widespread use. As an alternative approach to SIT, genetic immunization has proven its potential to cure and to prevent from allergic reactions in animal models. The Th1-biased immune response induced by intradermal or intramuscular injection of plasmid DNA obviously enables to prevent from an allergic reaction as well as to balance an established Th2-type response. However, the major restriction of genetic immunization (especially concerning its clinical use) is the requirement of large doses of DNA. To overcome this problem, the first aspect of the present project will be the application of a novel type of genetic vaccines, the so-called self-replicating DNA vaccines or DNA replicons, for allergy protection and treatment. Intradermal immunization with these constructs induces the desired Th1-biased immune response with only nanogram quantities of injected DNA. The second aspect of the project will cover the development of strategies for minimizing the risk of anaphylactic side effects. We will develop (i) genetic vaccines encoding allergen variants or derivatives, which still retain the induction of T-cell responsiveness but display reduced allergenic reactivity upon sensitization with the wildtype allergen, (ii) genetic vaccines targeting their gene products to proteasomal degradation, thereby preventing the formation of native allergen, but keeping the potential for T cell activation, and (iii) genetic vaccines, which co- express tolerance-inducing cytokines such as IL-10 and TGF-ß. Summing up, the project approaches should lead to the development of safety-optimized and effective genetic vaccines for the use in future clinical studies.