T‐cell targeted pulmonary siRNA delivery for the treatment of asthma. (8th April 2020)

• Record Type: Journal Article
• Authors: Keil, Tobias W. M.; Baldassi, Domizia; Merkel, Olivia M.
• Is Part Of: Wiley interdisciplinary reviews. Volume 12:Number 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-04-08
• Subjects: asthma -- inhalation -- siRNA -- T cells; Nanomedicine -- Periodicals; Nanotechnology -- Periodicals; Biotechnology -- Periodicals; Ultrastructure (Biology) -- Periodicals; 610.28
• DOI: 10.1002/wnan.1634
• Languages: English
• ISSNs: 1939-5116

Abstract

Abstract: 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 Abstract : Polyplexes made from siRNA complexed with Tf‐PEI and Mel‐PEI are shown to be specifically taken up by ATCs facilitating endosomal release necessary for efficient gene silencing. By spray drying, dry powders are obtained for pulmonary delivery as therapeutic option in the treatment of asthma.