Scientists at UMass Chan Medical School have developed a technology to deliver gene therapy directly to lung tissue through intranasal administration, a development that could potentially create a new class of treatments for lung disease.

Published in The Proceedings of the National Academy of Sciences, the study by a multidisciplinary team of RNA biologists, chemical biologists, immunologists and virologists describes the delivery of siRNA molecules locally to lung tissue. It is the first demonstration that multimeric siRNA molecules can be taken up into the lung after intranasal administration and achieve safe and robust genetic silencing. More importantly, the platform technology is adaptable for other pulmonary diseases such as pulmonary fibrosis and respiratory viruses.

Using the novel chemical scaffold, Dr. Hariharan and colleagues successfully delivered stabilized divalent siRNA molecules to animal models that blocked SARS-CoV-2 and prevented infection.

“The lung is a tough organ to get RNA molecules to because it’s very sensitive to potential toxins and particles that can cause immune reactions,” said Hariharan.

Small interfering RNA (siRNA) is a class of short, noncoding RNA molecules, only 20 to 24 base pairs in length, found in cells and that can be produced synthetically. They are part of the RNA interference (RNAi) system first identified by 2006 Nobel Laureate Craig Mello at UMass Chan Medical School. siRNA molecules interfere with the expression of genes by binding to messenger RNA (mRNA) after it’s been transcribed from the genome. Once bound to its target, the siRNA recruits cellular proteins that cut the mRNA, which is then degraded naturally by the cell before it can produce the corresponding protein. This prevents the cell from making proteins from that specific genetic sequence.

“Optimizing the chemical scaffold is key to the clinical application of siRNA therapeutics in lung tissue,” said Watts. “There are other delivery mechanisms, such as lipid-encased RNAs, that work well for tissues such as the liver, but this approach isn’t easy to adapt for the lung.”

By making the siRNA molecule with chemically modified nucleotides, Watts and colleagues can protect the siRNA from being degraded too quickly by the cells. This keeps the siRNA in the lung longer, and enables it to slip past the immune response.

Reference: https://www.umassmed.edu/news/news-archives/2023/04/umass-chan-scientists-deliver-sirna-therapy-to-lung/