The Halle Research Center for Drug Therapy (HRCDT) and the Halle chapter of the German Pharmaceutical Society (DPhG) cordially invite you to a lecture by

Prof. Dr. Olivia Merkel
Ludwig Maximilians University Munich

RNA delivery: challenges and progress

Delivery poses a significant challenge in realizing the potential of RNA medicines. While existing siRNA drugs target the liver, the lung offers opportunities for treating previously untargeted conditions using RNA therapeutics. Our lab designs inhalable and biocompatible nanocarriers to efficiently deliver siRNA to the lung. Biodegradable cationic Poly(beta-amino ester)s can facilitate nucleic acid delivery both in vitro and in vivo. Instead of the traditional trial-and-error approach, a combination of Design-of-Experiments (DoE), Molecular Dynamics Simulations, and Machine Learning (ML) expedites the discovery and optimization of siRNA nanocarriers, saving wet-lab resources. Our previous work yielded hydrophobically-modified spermine-based Poly(β-amino ester)s (PBAEs), which efficiently encapsulate siRNA into sub-100 nm nanoparticles with a low polymer excess ratio (N/P 5-10). These formulations resulted in up to 95% GFP silencing in vitro and successfully delivered siRNA for gene silencing in various culture models, including air-liquid-interface cultures and targeting mutated KRAS expression, inhibiting cell migration. Comparing polymer backbones, polyacrylamide (PAA)-based polyspermines showed more efficient siRNA delivery and gene silencing in air-liquid-interface cultures compared to Lipofectamine, with a better safety profile both in vitro and in vivo. When administered intratracheally in mice, PAA-based polyplexes were efficiently taken up by Type II pneumocytes and avoided recognition by lung macrophages. In human lung tissue from patients suffering from lung fibrosis, the former mediated more efficient PAR2 silencing than commercially available transfection reagents, resulting in more pronounced reduction of Collagen I levels. Further in vivo efficacy experiments are ongoing, but based on our preliminary data, polyspermines appear highly promising for RNA formulation and delivery, with an excellent safety profile in the lungs.

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