OSU researchers are taking an important step toward improving and extending the lives of cystic fibrosis patients

OSU researchers are taking an important step toward improving and extending the lives of cystic fibrosis patients

Researchers at Oregon State University and Oregon Health & Science University have taken a critical step toward improving and extending the lives of cystic fibrosis patients, who suffer from chronically blocked airways and a dramatically shortened life expectancy.

The team of scientists and clinicians has developed inhalable lipid nanoparticles that can effectively deliver messenger RNA to the lungs, stimulating lung cells to produce the protein that thwarts the disease.

The results were published in ACS Nano.

The research was led by postdoctoral fellow Jeonghwan Kim and Gaurav Sahay, an associate professor of pharmaceutical sciences in the OSU College of Pharmacy, who is studying lipid nanoparticles, or LNPs, as gene delivery vehicles with a focus on cystic fibrosis. Lipids are fatty acids and similar organic compounds, including many natural oils and waxes, and nanoparticles are tiny pieces of material ranging in size from one to 100 billionths of a meter.

Cystic fibrosis is a progressive genetic disease that results in persistent lung infection and affects 30,000 people in the United States, with about 1,000 new cases identified each year. More than three-quarters of patients are diagnosed by age 2, and despite steady progress in alleviating complications, the median life expectancy is still only 40 years.

A faulty gene - the cystic fibrosis transmembrane conductance regulator (CFTR) - causes the disease, which is characterized by lung drying and mucus buildup that blocks the airways.

In 2018, Sahay and other scientists and clinicians at OSU and Oregon Health & Science University demonstrated proof of concept for a new therapy: loading chemically modified CFTR messenger RNA into LNPs, opening the door to molecular medicine that could be inhaled at home.

The mRNA-loaded nanoparticles cause cells to correctly produce a protein needed to regulate chloride and water transport, which is critical for healthy respiratory function.

In the current mouse model study, Sahay and collaborators, including Kelvin MacDonald, an OHSU physician who treats cystic fibrosis patients, designed and manufactured nanoparticles with special properties that allow them to deliver their molecular payload to lung cells more effectively.

Lipid nanoparticles have been successful in delivering mRNA in vaccines, but inhalation-based mRNA therapy has remained challenging. LNPs tend to break apart due to shear stress during aerosolization, resulting in ineffective delivery.”

Gaurav Sahay, Associate Professor of Pharmaceutical Sciences, OSU College of Pharmacy

What's needed, he explains, are LNPs that are tough enough to withstand aerosolization and penetrate sticky mucus, but still maneuverable enough to perform a key movement once inside a cell - they must escape from a compartment known as an endosome into the cytosol, where the transferred genes can perform their intended function.

Sahay co-authored a paper in 2020 that showed that LNPs containing phytosterols—plant-based molecules chemically similar to cholesterol—were ten to a hundred times better at carrying out endosomal escape; The phytosterols changed the shape of the nanoparticles from spherical to polyhedral and caused them to move faster.

In the latest study, researchers used the cholesterol analog beta-sitosterol with a PEG (polyethylene glycol) lipid to address durability and maneuverability challenges.

“Increased PEG concentrations in the LNPs provided better shear strength and mucus penetration, and β-sitosterol created this polyhedral shape that facilitates escape from the endosome,” Sahay said. “Inhaled LNPs resulted in localized protein production in the mouse lung without toxicity, either pulmonary or systemic, and repeated administration resulted in sustained protein production in the lung.”

The National Heart, Lung and Blood Institute and the Cystic Fibrosis Foundation supported this research, which also included Elissa Bloom, Christopher Acosta and Antony Jozic from the College of Pharmacy, as well as scientists from Duke University.

To further push the boundaries of LNP-based science and medicine, Sahay and four other Oregon State University faculty recently launched the Center for Innovative Drug Delivery and Imaging (CIDDI).

CIDDI, hosted by the College of Pharmacy, received a $700,000 grant from the MJ Murdock Charitable Trust to purchase equipment for a manufacturing facility in translational nanomedicine – the fusion of nanoparticle theory and technology to prevent and treat disease.

The grant was awarded to Sahay and seven other investigators from OSU and OHSU. CIDDI is located in the Robertson Life Science Building, which was built in Portland's South Waterfront to house scientists from Oregon State University, OHSU and Portland State University.

OSU and OHSU are providing $600,000 in additional funding to further strengthen partnerships between Oregon universities and deliver next-generation translational nanomedicine to benefit Oregon and beyond, Sahay said.

Sahay and Oleh Taratula from the College of Pharmacy are the directors of CIDDI, and pharmacy colleagues Olena Taratula, Adam Alani and Conroy Sun are also founding members.

Source:

Oregon State University

Reference:

Kim, J., et al. (2022) Engineering lipid nanoparticles for enhanced intracellular delivery of mRNA via inhalation. ACS Nano. doi.org/10.1021/acsnano.2c05647.

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