A potential therapy delivered through nanoparticles enables production of the normal, healthy form of the key CFTR protein in cystic fibrosis (CF), a new study suggests.
The research, “Lipid Nanoparticle-Delivered Chemically Modified mRNA Restores Chloride Secretion in Cystic Fibrosis,” was published in the journal Molecular Therapy.
Although CF is a monogenic disorder, which means it is caused by alterations in a single gene (the cystic fibrosis transmembrane conductance regulator, or CFTR), more than 300 different disease-related mutations in CFTR have been discovered. This means significant variance in disease progression from patient to patient.
Patients with CF may be treated with approaches that improve CFTR function, such as Vertex Pharmaceuticals‘ Orkambi (ivacaftor/lumacaftor) or Kalydeco (ivacaftor). However, those therapies’ cost and possible adverse effects often lead to patients discontinuing treatment. Also, about 30 percent of patients carry a gene mutation not enabling a protein rescue approach, while potential toxicity issues limit these therapies to young patients.
The study from Oregon State University and Oregon Health & Science University provided proof-of-concept evidence for an improved therapy approach. The new strategy involves loading chemically modified messenger RNA (mRNA, generated from DNA in gene expression) from CFTR into lipid (fat)-based nanoparticles, a treatment that could be inhaled at home.
Instead of correcting the activity of the mutant protein underlying CF’s typical mucus buildup and lung dryness, these nanoparticles allow for the generation of the correct, healthy protein. This enables cells to efficiently regulate the transport of chloride and water, which is key for normal respiratory function.
“It’s a platform technology for correcting monogenic disorders and allows the same therapy to be effective for treating all cystic fibrosis patients,” Gaurav Sahay, PhD, the study’s senior author and a professor of pharmaceutical sciences, said in a press release.
Sahay said the new approach “can be repeatedly administered to a patient and the effects are reversible if someone needs to stop the therapy for any reason.”
The scientists successfully tested the mRNA-loaded nanoparticles in patient-derived bronchial epithelial cells, which are a defensive barrier involved in cleaning the respiratory airways, and in mice with genetic deletion of CFTR.
Results in patient-derived cells showed an increase in the level of CFTR protein located in the cell membrane, as well as improved chloride transport.
In mice, nasal application of the therapy restored CFTR-mediated chloride release to airway epithelia for a minimum of 14 days. On day three after treatment, the activity of CFTR peaked up to 55 percent of the total chloride secretion of healthy mice. This magnitude of response “is comparable with outcomes observed in the currently approved drug ivacaftor [Kalydeco],” the researchers wrote.
“We made a one-size-fits-all treatment,” said Ema Robinson, the study’s first author. “We’re adding back the gene that makes the protein so the airways can be rehydrated, and we can adjust the dosage as the disease gets better.”
Robinson also believes that repeated doses of nanoparticles are safe, and enabling treatment at home likely will increase patient compliance. This would be an advantage over existing options.
“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,” she 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.”
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