Systemic Delivery Following Pulmonary Administration of Large-Molecule Nucleic Acid Drugs

Pulmonary administration of small molecule drugs is commonly used to treat asthma and other respiratory diseases as a convenient approach to provide local therapy to the lung.  Localized administration requires a lower dose than is needed with systemic drug administration and also minimizes side effects.  In the research setting, pulmonary administration has been used to deliver investigational nucleic acid drugs to treat various disorders, including hard-to-treat viral infections like influenza or respiratory syncytial virus.

In the December 2011 issue of Molecular Therapy, Moschos and colleagues studied pulmonary delivery of chemically modified antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) in mice. The ASOs employed a chimeric design with mixed DNA and LNA (locked nucleic acids) residues with either unmodified phosphodiester (PO) or modified phosphorothioate (PS) linkages. The siRNAs used a mix of RNA and 2’-O-methyl RNA residues with unmodified PO linkages. The authors employed a novel method of tissue disruption followed by cell sorting to study the uptake and functional effects of the compounds in different cell types within the lung, such as macrophages (immune cells) or pulmonary epithelial cells. None of the synthetic nucleic acids showed any functional effects in any of the cell types present in the lungs. Unexpectedly, a significant amount of the administered dose of both classes of nucleic acids was absorbed into the circulation and the PO ASOs and siRNAs were rapidly excreted by the kidneys into urine. The PS-modified ASOs, on the other hand, were less rapidly excreted and a significant fraction accumulated in the liver.

These observations indicate that systemic delivery of large molecule drugs was successfully achieved by inhalation. They compared the ability of intravenous vs. pulmonary delivery of a PS-LNA ASO targeting ApoB (a gene involved in cholesterol transport) to reduce ApoB gene expression in the mouse liver and found that pulmonary administration was almost as effective as intravenous injection.

This is truly a remarkable discovery and may pave the way for use of inhaled nucleic acid drugs as an alternative to intravenous injection.