New grant funds research into airway stem cells as a long-lasting CF therapy

Two U.S.-based researchers aiming to help gene-corrected airway stem cells grow and survive long enough to repair lung tissue — with the goal of developing a long-lasting treatment for cystic fibrosis (CF) — have received a grant from the nonprofit Emily’s Entourage.

This type of stem cell therapy may ultimately provide new treatments for people with CF who are not eligible for available options targeting specific gene mutations, according to a press release from the nonprofit. The scientists say they’re working to engineer receptor proteins to give the stem cells responsible for regenerating the airway an advantage, helping them grow.

Emily’s Entourage announced that its first translational research grant of the year was awarded to Sriram Vaidyanathan, PhD, principal investigator at Nationwide Children’s Hospital and assistant professor at The Ohio State University, and Kyle Cromer, PhD, assistant professor at the University of California, San Francisco.

“We are incredibly excited about the promise of gene therapy for the CF community … but there are still significant challenges to overcome to make that promise a reality,” Emily Kramer-Golinkoff, who cofounded Emily’s Entourage, wrote in an email to Cystic Fibrosis News Today.

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An inherited disease, CF is caused by mutations in the CFTR gene that result in abnormally thick and sticky mucus that accumulates in the lungs and other organs. A widely used type of therapy called CFTR modulators can help ease symptoms of CF by increasing the functionality of the protein encoded by the CFTR gene.

These treatments are approved for people with specific mutations, however, so not everyone with CF is eligible for them.

Gene therapy works differently: It aims to correct or replace the mutated CFTR gene. However, gene-corrected airway basal cells — long-lasting stem cells that continually produce new cells to line the airways — do not naturally grow faster than uncorrected cells. That can prevent gene-corrected stem cells from becoming numerous enough to provide a lasting benefit, according to the researchers.

“This research explores a new tool that could help make future CF gene therapies far more effective and durable, bringing us closer to treatments that can save the lives of people with CF who are still waiting with bated and fading breath,” Kramer-Golinkoff said. She note that this work is “especially [important] for the final 10% [of CF patients] that do not benefit from CFTR modulators.”

Researchers say new system ’tilts the balance’ in CF

The two newly awarded researchers are developing synthetic receptors — proteins that receive signals and trigger responses — designed to give gene-corrected stem cells a temporary growth advantage. These lab-made receptors mimic signals that naturally help airway stem cells to grow.  The receptors can be activated by a small molecule.

When turned on, the synthetic receptors will signal stem cells to multiply and spread through the airway lining, or epithelium. Once enough have populated the airways, the signal can be turned off. This temporary control is intended to help gene-corrected stem cells take over without permanently changing their behavior, the researchers noted.

“Gene correction alone may not be enough if corrected cells can’t outcompete diseased tissue,” Vaidyanathan said. “We’re developing a system that temporarily tilts the balance — allowing repaired cells to expand and potentially improve the durability of gene-based therapies.”

One of the biggest challenges in gene therapy isn’t just fixing the gene — it’s ensuring those corrected cells can persist and repair tissue over time.

Vaidyanathan and Cromer will test two groups of synthetic receptors for their ability to selectively increase the number of gene-corrected airway basal cells. The testing will also assess whether the new cells preserve their ability to differentiate, or develop, into the different healthy cells needed to repair and maintain lung tissue.

“One of the biggest challenges in gene therapy isn’t just fixing the gene — it’s ensuring those corrected cells can persist and repair tissue over time,” said Chandra Ghose, PhD, chief scientific officer at Emily’s Entourage. “This project introduces a creative synthetic biology strategy to address that challenge and help advance more durable treatment approaches for CF.”

Emily’s Entourage supports research into CF to develop new treatments and a cure for patients who cannot benefit from available mutation-targeted treatments. Its grant program, which includes translational and collaborative grants as well as venture investments, provides funding to accelerate this type of research. The nonprofit is based in Pennsylvania and has raised more than $20 million for CF research.