CF gene therapy delivery to lungs could be enhanced with new device

Experiments show MAP delivers payload better than standard inhaler

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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One beaker halfway filled with liquid is shown in front of two others will illustrations of DNA strands in them.

Researchers have developed a device that could improve gene therapy delivery to the lungs for people with genetic conditions such as cystic fibrosis (CF).

In a series of preclinical experiments, the research team showed that its device could deliver a therapeutic payload to cells better than a standard inhaler while also avoiding damaging the therapy’s carrier molecule.

“This study demonstrates a marriage between new devices and formulation science that might hugely impact human health,” Gaurav Sahay, PhD, professor at Oregon State University and the study’s senior author said in a university press release.

The study, “Microfluidic Platform Enables Shearless Aerosolization of Lipid Nanoparticles for mRNA Inhalation,” was published in ACS Nano.

Gene therapies add, remove, or edit genetic material in order to address the underlying cause of a disease. The approach is of interest in CF, where mutations in the CFTR gene lead to a lack of functional CFTR protein, which results in thick and sticky mucus building up in organs, especially the lungs, driving the symptoms of the disease.

The idea is that a healthy CFTR gene or its messenger RNA (mRNA) — a type of genetic blueprint molecule made from DNA that contains instructions for making a functional protein — could be delivered to patients, giving the body the genetic tools it needs to make a working protein.

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MAP delivers genetic payload better

Sahay and his colleagues are developing lipid nanoparticles as an mRNA therapy delivery vehicle and focusing on therapeutic applications in CF. These tiny carriers, made up of fatty molecules, have properties that make them favorable for getting into cells and avoiding degradation, so they’re of interest for delivering genetic payloads.

The hope is that nanoparticles containing CFTR mRNA, or genetic material relevant to to other lung diseases, could be inhaled directly into the lungs.

Inhaled medications are commonly delivered through a vibrating mesh nebulizer, which converts a liquid medication into a mist-like suspension of particles, or an aerosol, for inhaling.

This approach might be problematic for delivering mRNA therapies, however. The forces that standard nebulizers use to disperse the mist generate shear stress that may damage nanoparticle carriers and limit their ability to carry genetic cargo. It’ll also cause the particles to clump together instead of spreading out evenly once they reach the lungs.

To overcome these barriers, the researchers have been collaborating with Oregon-based startup Rare Air Health to test a delivery method called a microfluidic aerosolization platform (MAP).

The device houses microfluidic chips and generates plumes, where the nanoparticles are released from channels in a spread-out manner without the type of force that causes shear stress with standard nebulizers.

Sahay likens the approach to an ink-jet cartridge for a printer, which “generates plumes to print words on paper.”

A series of preclinical experiments in cell cultures and mouse models “demonstrated the superiority of this device in generating aerosolized nanoparticles as compared to clinically used vibrating mesh nebulizers,” Sahay said. “The additional cool thing is that this device can be digitally controlled and Rare Air is developing prototypes for human use.”

The microfluidic approach avoided nanoparticle clumping, and prevented nanoparticle damage and loss of mRNA encapsulation. It was also associated with better uptake of the mRNA payload in cell cultures over the standard nebulizer. In mice, the device led to mRNA uptake in lung cells without signs of toxicity.

“This MAP may represent an advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles,” the researchers wrote.

The study was supported by funding from Rare Air Health and the National Heart, Lung, and Blood Institute.