OSU researcher’s goal: Universal cystic fibrosis treatment

A pharmaceutical sciences researcher at Oregon State University has received a five-year, $3.3 million grant from the National Institutes of Health to develop a way for cystic fibrosis patients to get molecular treatment via an inhaler, a potential vast improvement over existing therapeutic methods.

The treatment would be designed to work on every cystic fibrosis patient, regardless of the specific genetic mutation behind his or her case.

Gaurav Sahay of the OSU/OHSU College of Pharmacy will collaborate with Kelvin MacDonald of Oregon Health & Science University, a scientist and physician who specializes in working with cystic fibrosis patients.

Sahay and MacDonald’s project is based around lipid nanoparticles carrying messenger RNA that can correct the underlying genetic defect that causes the disease: a mutation in the gene that encodes an ion transporter protein.

“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. “That’s the novelty of the system.”

Cystic fibrosis is a progressive genetic disorder that results in persistent lung infection and afflicts 30,000 people in the U.S., with about 1,000 new cases diagnosed every year.

More than three-quarters of patients are diagnosed by age 2, and despite steady advances in alleviating complications, the median life expectancy of cystic fibrosis patients is still just 40 years.

One faulty gene – the cystic fibrosis transmembrane conductance regulator, or CFTR – causes the disease, which is characterized by lung dehydration and mucus buildup that blocks the airway.

To date more than 1,200 different disease-conferring mutations have been found, meaning there is a lot of variance from patient to patient in how the disease progresses.

Treatment to “rescue” the mutant protein produced by the bad gene is available to some patients, although almost one patient in five discontinues therapy because of the high cost and the side effects.

Also, about 30% of patients have a gene mutation with no protein rescue treatment option, and toxicity concerns limit protein rescue therapy to patients older than age 6.

The new treatment approach involves loading chemically modified CFTR messenger RNA into the lipid-based nanoparticles, creating molecular medicine that could simply be inhaled at home.

Rather than trying to mend the patients’ existing mutant protein, the mRNA-loaded nanoparticle approach causes the cells to make the correct protein – allowing cells to properly regulate chloride and water transport, which is critical to healthy respiratory function.

The approach – adding back the gene that makes the protein – can function as a one-size-fits-all treatment and should vastly help in the area of patient compliance.

“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,” Sahay said. “And the drugs often make them quite sick. We hope that repeated doses of nanoparticles would not make people sick, and would also let patients stay at home and likely increase compliance.”