Characterization of the physico-chemical conditions and immune-function at the human olfactory mucosa

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The human respiratory tract, and in particular the nasal cavity, has a large absorptive surface with different types of epithelia namely respiratory, olfactory, squamous and transitional mucosa. In addition, the nasal mucosa provides a very important immune function since countless inhaled pathogens are filtered in the upper airways and transported via mucocilliary clearance to the nose-associated lymphoid tissue (NALT). Like other mucosal tissues the nasal cavity is very suitable for the administration of drugs. Clinical data suggest that dependent from the site of administration three different delivery routes to three distinctive pharmacological compartments can be targeted: the olfactory mucosa enables brain delivery and bypasses the blood brain barrier, the very well vascularized respiratory epithelium targets the central (blood) compartment and interactions at the NALT trigger immune reactions as known from administration of intranasal vaccines. However, the contact of therapeutics with the NALT harbors also the risk of immunogenicity, a serious safety issue. Very interestingly, we could recently demonstrate an efficient uptake of IgG antibodies via Fc receptors in the olfactory mucosa and from there a rapid distribution to the CNS.However, very few data are available how to target the different routes separately. We could demonstrate in a previous study that targeting the olfactory or respiratory region results in specific bioactivity in the CNS or the periphery. The conditions and targets of self-administered drugs are critical for a save and efficient therapy. In previous studies we have determined the limited suitability of aerosols for region-specific delivery, the influence of aerosol generation on protein aggregation and the effects of protein formulation on stability and mucosal permeation. Furthermore, we have developed a standardized in vivo model to administer drugs specifically to a nasal region.In this project, we will characterize with a holistic approach the human olfactory mucosa, its mucus and clearance and its immune function. The results of this project will enable us to better understand olfaction and to design novel drug delivery strategies for a regional-specific and thereby safe intranasal drug administration targeting either the CNS or the local mucosal immune system of the airways to fight infectious diseases.