Laura Tasca1, Valentina Sala1, Xiao-Yann Huang3, Rosy Bonfante3, Bernadett Boda3, Samuel Constant3, Charlotte Dunne4, Natascha Hartl4, Katrin Radloff4, Nourhan Kawaji4, Dimitrios Goundis¹, Alessandra Ghigo1,²
1Kither Biotech, Via Nizza 52, Torino (TO), 10126, Italy
2Dipartimento di Medicina Molecolare, Università di Torino, Via nizza 52, Torino (TO), 10126, Italia
3Epithelix, 18 chemin des Aulx, CH-1228 Plan-les-Ouates, Switzerland
4Pantherna Therapeutics GmbH, Neuendorfstrasse 20b, D-16761 Hennigsdorf
Summary
Inhaled mRNA therapies have emerged as a promising approach for genetic and rare diseases such as cystic fibrosis (CF), where only protein replacement can restore or compensate for dysfunctional or missing proteins. However, effective mRNA delivery, uptake and expression face several barriers, including mucus penetration, degradation, and endosomal escape. Add-on treatments that enhance the function of mRNA-based protein replacement therapies may further improve clinical efficacy.
KIT2014, a dual phosphodiesterase (PDE) 3/4 inhibitor developed by Kither Biotech, was evaluated as a novel add-on therapy for its ability to improve ciliary function, a key determinant of airway clearance, and to enhance the efficacy of inhaled mRNA-based treatments in diseases such as CF.
Using the MucilAir™-Pool model, KIT2014 was tested at multiple concentrations, assessing ciliary beating frequency (CBF) as the primary endpoint and epithelial integrity as the secondary endpoint. Apical administration of KIT2014 at 30 μM (5.65 μg/cm²) without prior mucus removal significantly increased CBF after 2 hours (p < 0.05) in fully differentiated human primary nasal epithelial cells, while preserving epithelial barrier integrity. All tested concentrations preserved transepithelial electrical resistance (TEER) after 6 hours of exposure.
These results demonstrate that KIT2014 significantly stimulates CBF while preserving epithelial integrity. This activity, combined with its ability to enhance CFTR gating, improve mucus hydration, reduce neutrophilic inflammation, and induce bronchodilation, provides a comprehensive approach to restoring airway function. This multimodal profile positions KIT2014 as a promising add-on therapy to enhance the performance of inhaled treatments, including future mRNA-based strategies for rare genetic diseases.