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 these patients 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 Donald Kohn, MD, a gene therapy pioneer who has successfully developed therapies for other single-gene disorders such as severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID.
“It’s like trying to get into Fort Knox,” said Dr. 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 Brigitte Gomperts, MD, and nanotechnologist Steven Jonas, MD, PhD. 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 Dr. Jonas, an assistant professor of pediatrics at UCLA Health.
New hope for cystic fibrosis patients without treatment options
Dr. Gomperts has always been driven by a simple goal: finding better treatments for her patients.
That pursuit has led her to spend more than 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,” Dr. Gomperts, a professor of pediatrics and pulmonary medicine at UCLA Health, 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,” Dr. 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 Dr. Kohn optimizes the gene-editing method, Dr. 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,” Dr. Jonas said. “Our nanoparticles are the packaging that helps transport the gene-editing machinery while shielding it from the body’s defenses.”
Ruby Sims, PhD, 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, Drs. 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,’” Dr. 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 such as muscular dystrophy and sickle cell disease.
“The beauty of this approach is its modularity — it’s like Legos,” Dr. 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,” Dr. Kohn said. “Science is also the most fun when you’re tackling these difficult problems together.”
