Researchers at UMass Chan Medical School have developed a small interfering RNA (siRNA) technology that is stable enough for inhalation into the lungs, where it can potentially treat diseases as diverse as asthma, pulmonary fibrosis, and viral infections such as COVID-19. siRNA is not typically stable enough to survive for long in the lungs, but the researchers chemically modified the constituent nucleotides to stabilize the molecules and help them to evade immune destruction. The technology is designed to silence genes that are crucial in disease processes. In a demonstration of the potential of the technique, the researchers created an siRNA treatment that targets a gene in SARS-CoV-2, and showed that it could reduce the translation of the gene by 60-80%, preventing COVID-19 infection in mice.
Fluoresce images of lung tissue after treatment (top, red), show local distribution of chemically modified siRNA and robust gene silencing in the lung.
As the weeks and months pass, researchers are busy creating the new treatments and diagnostic technologies that will hopefully permanently consign COVID-19 from a world-stopping contagion to a routine illness that is easily mitigated. With any luck, these innovations will also help us treat a host of other diseases. Crises can bring out the best in (some of) us it seems.
This latest technology ticks a lot of these boxes. It is based on siRNA, which are short strands of RNA (20-24 bases in length) that can bind to messenger RNA (mRNA) that has been transcribed from the genome, and then recruit proteins that cleave the mRNA strands into pieces. This ultimately prevents the mRNA from being transcribed to a protein and effectively silences the targeted gene.
“If you think of the cell as being a huge block of text in a word processing program, siRNA is like a search and find function; using the right combination of letters you can find any word in the text, or in this analogy, any genetic sequence,” said Jonathan K. Watts, a researcher involved in the study. “Using siRNA we can subvert the protein-production process by deleting specific disease-causing mRNA sequences before they are made into a protein, allowing us to treat the disease.”
So far, the researchers have developed an siRNA treatment for COVID-19. To achieve this, they designed the siRNA sequence so that it would target viral mRNA inside infected lung cells. The siRNA was stable enough to be delivered to the lungs intranasally. They chose an mRNA target that is found in all known SARS-CoV-2 variants, and which they hypothesized was essential for viral survival.
In a mouse model, the siRNA could be delivered to the lungs, where it reduced protein expression of the targeted gene by 60-80%, effectively preventing infection. Ensuring that the siRNA molecules were stable was an important aspect of this success. “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.”
Study in journal PNAS: Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection