A pharmaceutical sciences researcher will use a five-year, $3.3 million grant from the National Institutes of Health (NIH) to develop an inhaled therapy for use by all cystic fibrosis (CF) patients, regardless of the genetic mutation underlying their disease.
Researcher Gaurav Sahay, PhD, of Oregon State University (OSU), plans to create a “one-size-fits-all” treatment based on inhalable nanoparticles that deliver necessary genetic material to airway cells to produce functional CFTR ion channels, which are absent or defective in people with CF.
“We want to come up with a way to make the nanoparticles stable enough to pass through the mucus in the patients’ lungs, but based on structural changes inside the nanoparticles, once in the cells they can release the RNA,” Sahay said in a press release.
“That’s the novelty of the system,” he added.
Sahay, an assistant professor at the college of pharmacy at OSU/Oregon Health Science University (OHSU), will develop the universal treatment with another OHSU professor, Kelvin D. MacDonald, MD, who specializes in working with CF patients.
Treatment with CFTR modulators to correct the defective CFTR protein, caused by a faulty CFTR gene, is only available to people who carry certain types of mutations. And 1 in 5 patients who can use the treatment stops therapy because of its high cost or side effects.
For the 30% of remaining patients — those with a gene mutation with no protein rescue treatment option — there is no specific therapy currently available.
The new approach involves loading chemically modified CFTR messenger RNA (mRNA) — molecules that serve as genetic blueprints for making proteins — into lipid, or fat-based nanoparticles, creating a product that could be inhaled at home.
Unlike CFTR modulators, which try to correct the mutant protein, the nanoparticles cause the cells lining the airways (airway epithelia) to make their own functional CFTR proteins. This will enable patients’ cells to properly balance the transport of chlorine ions and water, which is essential for producing a fluid mucus, and avoid the mucus buildup and lung dryness characteristic of the disease.
Last year, Sahay and his lab published a study with proof-of-concept evidence providing support to their strategy. They successfully tested the mRNA-loaded nanoparticles in patient-derived bronchial epithelial cells, which started to show more CFTR protein at the cell membrane, as well as improved chloride transport.
In mice, nasal application of the therapy also restored CFTR function in airway cells, reaching a magnitude of response comparable to the currently approved therapy ivacaftor (brand name Kalydeco, marketed by Vertex Pharmaceuticals).
Researchers believe mRNA therapy via nanoparticle delivery represents a powerful alternative for the transfer of genetic material to cells, such as airway epithelia.
“If you have a kid you have to bring to the hospital six hours a week on three different days, that could become logistically difficult and you might not always be able to make it happen. And the drugs often make them quite sick,” Sahay said.
“We hope that repeated doses of nanoparticles would not make people sick, and would also let patients stay at home and likely increase compliance,” he concluded.