cystic lung disease :: Article CreatorBreathing New Life: Working Toward An Inhalable Gene Therapy For Cystic Fibrosis
Imagine a future where treating cystic fibrosis is as simple as taking a deep breath. That's exactly what a team of pediatric physician-scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA is working to achieve.
Cystic fibrosis is a life-threatening genetic disease that clogs the lungs with thick, sticky mucus, leading to chronic infections and severe organ damage. Despite breakthrough medications that have been transformative for some, the drugs come with significant limitations: they don't work for everyone, can cost millions over a lifetime and, most critically, don't address the root cause of the condition. Without a curative treatment, the disorder remains a ticking clock for patients who don't respond to existing drugs, many of whom face respiratory failure by their 30s or 40s.
The disease is caused by mutations in one gene — cystic fibrosis transmembrane conductance regulator, or CFTR — making it, in theory, an ideal candidate for gene-editing technology. However, there's a unique challenge of delivering a gene therapy to the target lung stem cells in cystic fibrosis, said Dr. Donald Kohn, a gene therapy pioneer who has successfully developed therapies for other single-gene disorders like severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID.
"It's like trying to get into Fort Knox," said Kohn, a UCLA distinguished professor of microbiology, immunology and molecular genetics. "There are multiple barriers — thick mucus, inflammation and the cells' location at the bottom of the airway."
To overcome these obstacles, he has joined forces with lung disease expert Dr. Brigitte Gomperts and nanotechnologist Dr. Steven Jonas. They're combining their diverse expertise to develop a targeted gene-editing system that can deliver a one-time treatment through a simple inhalable mist.
"Think about it like breathing in a CRISPR-Cas9 gene-editing package," said Jonas, an assistant professor of pediatrics at UCLA.
New hope for cystic fibrosis patients without treatment options
Gomperts has always been driven by a simple goal: finding better treatments for her patients.
That pursuit has led her to spend over 20 years studying stem cells of the airway, which are lung stem cells nestled deep within the airway walls that serve as targets for gene correction in the impacted lungs.
"These are the cells that continuously renew and generate the specialized cells responsible for keeping mucus hydrated and the airways clear," Gomperts, a professor of pediatrics and pulmonary medicine at UCLA, explained.
Although cystic fibrosis is a single gene mutation, there are more than 1,000 different ways the CFTR gene can mutate in patients. When functioning properly, this gene produces a protein that regulates the vital flow of water in and out of the lung stem cells, maintaining mucus at the right consistency.
In cystic fibrosis, mutations in the gene either produce proteins that don't work properly or, in more severe cases, prevent protein production entirely.
The currently available "miracle" drugs work only when there are some proteins to fix. For the 10%–20% of patients with null mutations who produce no protein at all, these medications offer no benefit.
These null mutations are known, and the Kohn lab is testing different gene-editing strategies to correct them.
"If you think of a sentence with 50 letters, any letter that's out of place will make the sentence nonsense," Kohn said. "We're moving forward with two approaches — fixing all the letters that are out of place by adding in a normal CFTR gene to override the inactive gene and developing methods to fix each of these mutations individually. We'll then evaluate what's most effective."
How nanotechnology is enabling gene editing for cystic fibrosis
While Kohn optimizes the gene-editing method, Jonas and his team are tackling the critical challenge of delivery: ensuring the gene-editing machinery reaches the lung stem cells, where the correction could last a lifetime.
Their solution harnesses the power of lipid nanoparticles — tiny molecular carriers designed to transport the gene-editing cargo directly where they're needed.
"Think of it like an Amazon delivery," Jonas said. "Our nanoparticles are the packaging that helps transport the gene-editing machinery while shielding it from the body's defenses."
Ruby Sims, a postdoctoral scholar in the Jonas lab, said it's of highest importance to target a precise location.
"It's not just about dropping off a package anywhere in the lungs," she said. "We need to deliver it to the right ZIP code, the right street, the right house. That's what our nanoparticles are engineered to do."
The team envisions delivering the therapy through an inhaler. Once administered, the nanoparticles would travel deep into the airways, delivering the gene-editing tools directly to the lung stem cells, where they can make a permanent repair.
Working collaboratively toward a cure for cystic fibrosis
For years, Gomperts, Kohn and Jonas have worked side by side in the pediatrics department treating children with cancer and blood disorders. But it took a chance lunch at the center's annual Stem Cell Symposium to bring them together on this project.
"I was really taken with this idea of gene therapy for cystic fibrosis and found myself sitting there thinking, 'Wow, I've got the exact experts who could actually make this happen,'" Gomperts recalled. "You have to know which cells you're targeting, how to reach them and the best way to fix the faulty gene, and among the three of us, we had all the pieces of the puzzle."
The UCLA Broad Stem Cell Research Center kickstarted the collaborative project with seed funding through its Innovation Awards Program. Promising preliminary results have since helped the team secure additional support from the California Institute for Regenerative Medicine, the Cystic Fibrosis Research Institute and the Cystic Fibrosis Foundation, helping move the project toward preclinical testing.
A platform to treat other genetic diseases
While the team's initial target is cystic fibrosis, the nanoparticle platform could be a transformative tool for treating other genetic lung diseases and even conditions like muscular dystrophy and sickle cell disease.
"Science is also the most fun when you're tackling these difficult problems together."
UCLA distinguished professor of microbiology, immunology and molecular genetics Dr. Donald Kohn
"The beauty of this approach is its modularity — it's like Legos," Jonas said. "We can swap in different gene-editing machinery and use the same delivery strategy to target and correct different genes."
For now, the researchers remain united by their mission to develop a one-time treatment that offers lasting benefits for patients with cystic fibrosis.
"Science is complicated, so multidisciplinary teams are the way to do it," Kohn said. "Science is also the most fun when you're tackling these difficult problems together."
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Pulmonary Rehabilitation Improves Training In Cystic Fibrosis Lung Transplant Candidates
March 28, 2025
3 min read
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Key takeaways:
Researchers captured exercise capacity measures during the first week of pulmonary rehabilitation to the session before transplant. Treadmill speed and two muscle training volumes went up between the two points. Between the first week of pulmonary rehabilitation and the last recorded session before transplantation, lung transplant candidates with cystic fibrosis had maintained or increased their rehabilitation measures, according to study data.
"The present study highlights the importance of physiological reserve as a majority of the CF lung transplant candidates in our study were younger compared to other pulmonary rehabilitation populations," J. Michael Nicholson, MD, FRCPC, adjunct professor at Schulich Medicine and Dentistry, Western University, told Healio.
"It is important to recognize that the aerobic and muscle training volume response improved despite frequent respiratory exacerbations and disease severity," he continued. "These findings in CF patients are also relevant to the non-CF population."
Dmitry Rozenberg
In this single-center, retrospective cohort study published in Respiratory Medicine, Nicholson, along with Dmitry Rozenberg, MD, PhD, FRCPC, respirologist at the University Health Network and assistant professor in the department of medicine at the University of Toronto, and colleagues assessed 86 adult lung transplant candidates (mean age, 32 years; 51% women; mean FEV1, 23% predicted) with CF to determine how pulmonary rehabilitation two to three times a week (median, 24-36 sessions) impacted various aerobic and muscle training volumes, as well as 6-minute walk distance (6MWD).
Nicholson noted that having at least one exacerbation was found in over three-fourths of the population (78%) in the period before transplantation. He also said over half (55%) needed hospitalization.
"An interesting finding in the present study was the high incidence of respiratory exacerbations in this CF cohort (July 2009-June 2019) awaiting lung transplantation," Nicholson told Healio.
Other important baseline characteristics included the use of supplemental oxygen by 88% of candidates and the use of home noninvasive ventilation by 37% of candidates, according to the study.
With pulmonary rehabilitation participation, researchers reported significant improvements in three measures between the first week of rehabilitation and the last measurement available before transplantation.
Treadmill speed was one of these measures, going up from 1.72 mph to 2.13 mph (mean of differences, 0.36; 95% CI, 0.23-0.48; P < .0001). The remaining measures pertained to training volumes. According to the study, biceps training volume rose from a median of 50 lbs*repetitions to 70 lbs*repetitions (mean of differences, 23; 95% CI, 11-35; P = .0003) and quadriceps training volume went up from a median of 30 lbs*repetitions to 50 lbs*repetitions (mean of differences, 19; 95% CI, 11-27; P < .0001).
In terms of 6MWD, the study highlighted that the first week measure did not significantly differ from the last available measure (421 m vs. 415 m). Other measures that did not significantly change from the measurement taken in the first week of pulmonary rehabilitation to the last available measurement included mean peak Borg dyspnea score after treadmill exercise, resting heart rate and end of treadmill exercise heart rate.
"With pulmonary rehabilitation we observed stability in the exercise capacity pre-transplant despite progressive, advanced lung disease and pulmonary exacerbations," Nicholson told Healio. "This is important as exercise capacity has been shown to be an important marker of mortality in lung transplant candidates."
Lastly, researchers analyzed the link between respiratory exacerbations and training volumes and found a significant reduction of 0.36 mph (95% CI, –0.67 to –0.04) in treadmill speed if candidates had at least one exacerbation.
"Respiratory exacerbations were an important contributor to deconditioning," Nicholson told Healio.
"Despite the fantastic improvements in CF care, unfortunately there will continue to be patients who require lung transplantation; those with or without highly effective modulatory therapy (HEMT) therapy," Nicholson added. "This article helps to demonstrate that there are ongoing training improvements that can be achieved by CF patients, despite very severe ventilatory limitations prior to the era of HEMT."
Looking ahead, Nicholson said studies will likely focus on HEMT.
"Although HEMT has changed the number of CF patients referred for lung transplantation, the focus on exercise training and lifestyle before referral for transplantation will be important," Nicholson told Healio.
"This will be especially true for those that are on HEMT and the fewer numbers awaiting lung transplantation, as we are not entirely sure how their exercise tolerance and outcomes will evolve," Nicholson continued.
For more information:
J. Michael Nicholson, MD, FRCPC, can be reached at michael.Nicholson@sjhc.London.On.Ca.
Dmitry Rozenberg, MD, PhD, FRCPC, can be reached at dmitry.Rozenberg@uhn.Ca.
Sources/DisclosuresCollapse
Disclosures:
Nicholson reports being supported by the Cystic Fibrosis Canada Clinical Fellowship. Rozenberg reports receiving research support from the Sandra Faire and Ivan Fecan Professorship and Temerty Faculty of Medicine. All other authors report no relevant financial disclosures.
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