Despite the large number of drugs available for the treatment of
asthma, in 5-10% of the patients this disease is not well controlled. While most treatments palliate symptoms, those suffering from severe and uncontrolled
asthma could benefit more from a therapeutic approach addressing the root problem. An
siRNA-based
therapy targeting the
transcription factor GATA3 in activated T helper cells subtype 2 (TH 2 cells), one of the key upstream factors involved in
asthma, could therefore represent a promising strategy. However, the difficult-to-transfect cell type has not extensively been explored for
nucleic acid therapeutics. In this regard, our group first identified a suitable pathway, that is,
transferrin receptor mediated uptake, to target efficiently and specifically activated TH 2 cells with a
transferrin-
polyethyleneimine (PEI) conjugate which forms polyplexes with
siRNA. This system, despite efficient uptake in activated T cells (ATCs) in vivo, suffered from poor endosomal release and was later improved by a combination with a
melittin-PEI conjugate. The new formulation showed improved endosomal escape and gene silencing efficacy. Additionally, in order to develop a clinically relevant
dosage form for pulmonary delivery of
siRNA we have lately focused on a dry
powder formulation by spray drying (SD) for the production of inhalable nano-in-microparticles. In proof-of-concept experiments,
DNA/PEI polyplexes were used in order to implement analytics and engineer process parameters to pave the way for SD also
siRNA containing polyplexes and more sophisticated systems in general. Ultimately, our efforts are devoted to the development of a novel treatment of
asthma that can be translated from bench to bedside and are reviewed and discussed here in the context of the current literature. This article is categorized under: Therapeutic Approaches and
Drug Discovery > Nanomedicine for Respiratory Disease Biology-Inspired Nanomaterials >
Nucleic Acid-Based Structures Biology-Inspired Nanomaterials >
Protein and Virus-Based Structures.