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Breathing 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."

My Two Children Were Born With The Same Rare Genetic Condition

Not many mothers anticipate having a child born with a rare genetic condition, never mind two children. Essex-based Emily Sibley found herself in this position seven years ago when her son Ricky was born. 

Now, full-time mum Emily, who is also a mother to four-year-old Freya with her partner Ricky Howe, tells her story to HELLO! as she shares the positive impact Great Ormond Street Hospital (GOSH) has had on her family this Mother's Day.

Emily's son has a rare genetic condition Ricky's birth

It was during Emily's 20-week scan with Ricky at Basildon Hospital in May 2018 that she was first told something was wrong. "He had a brightness on his bowel and they said it could be a sign of Cystic Fibrosis (CF)," Emily remembers. "We were really shocked."

Emily was shocked to hear Ricky had a genetic condition

CF is a condition that can cause breathing and digestive problems. While there is currently no cure, there are medications to help with battling infection. In June 2018, Emily noticed reduced movement in her unborn son and was referred for extra scans and kept in hospital for monitoring. She and her partner Ricky had blood work done that revealed that they both carried the CF gene. 

When doctors discovered Ricky's bowel had perforated, Emily went for a weekly scan at the hospital. She also had extra fluid that needed draining. However, on the day she was meant to be getting the fluid drained, Emily went into labour. 

"It was terrible," Emily says. "It's scary because you just don't know what the outcome was going to be."

Ricky has previously spent time in intensive care

Ricky's bowel was operated on during his second day of life at Norfolk and Norwich Hospital, where he remained in intensive care for three months. Ricky was diagnosed with Cystic Fibrosis at two weeks old. 

Meeting the staff at Great Ormond Street

Ricky was first admitted to Great Ormond Street Hospital (GOSH) in November 2017, spending two weeks in intensive care and a week on the ward after contracting bronchitis.

Ricky and Freya receive treatment at Great Ormond Street Hospital

When he was just three-and-a-half months old, he was rushed back to intensive care after he started having difficulty with his breathing. 

"The first year of his life was the worst, in and out of hospital. Catching all sorts of infections," Emily says. "Ricky's dad would get the train every day after work to visit us in hospital. 

Freya and Ricky were both diagnosed with cystic fibrosis as babies

"We were all tired. I used to cry when he left every day," Emily recalls. "We all felt different emotions – I'd never spent any time in hospital before having Ricky and I just couldn't cope with it."

Ricky got chest infections regularly as he was born prematurely at 32 weeks. He spent a lot of time during the first year of his life at GOSH with complications related to his Cystic Fibrosis diagnosis. 

Ricky and Freya support eachother

But the staff on hand provided the support the family needed. "They were brilliant," Emily recalls, explaining how in September 2023, Ricky began a new treatment Kaftrio and Kalydeco - a tablet he takes every day. It helps with improving quality of life and has reduced Ricky's hospital stays. "Some of the nurses are still there now and they feel like family."

In September 2023, Ricky began a new treatment Kaftrio and Kalydeco

Every three months, Ricky has to spend two weeks at GOSH for treatment for the conditions. The treatment involves two weeks of IV antibiotics – Caftazidine every eight hours and tobramycin once a day on an IV pump for 30 minutes. He also has a 7% nebuliser with physio after. Once at home, Ricky has physio every day and two other nebulisers twice a day. 

Freya's story

In November 2019, Emily fell pregnant with her daughter Freya, who was also diagnosed with CF at two weeks old. "The day I found out I was so upset. I was so emotional, I just kept crying," Emily says. "But then the next day I was fine because I thought, 'I'm already going through it with Ricky, nothing's going be different. I know what I'm doing'."

Freya also spent time in hospital as a baby

The staff at GOSH explained the importance of keeping on top of Freya's medication to prevent her from catching an infection from Ricky and vice versa. However, Freya, who was born in August 2020, caught bronchiolitis the December after she was born, meaning she spent her first Christmas in GOSH. 

Freya also has cystic fibrosis

"I was really dreading it because when you are sick at Christmas, you just want to be at home with your family," Emily says. However, the staff at GOSH made it as special as possible. 

Freya is admitted to GOSH every three months

"They brought really lovely presents around for Freya and they'd give us tickets so we'd go out to the canteen and get a Christmas dinner. It was really nice," she recalls.

The Play team at Great Ormond Street

With Freya being admitted to GOSH every three months and Ricky every six months to receive IV antibiotics to sustain their immune system, they have also benefited from the Play team, funded by Great Ormond Street Hospital Charity (GOSH Charity). "They are brilliant. They come into our room at least twice a day to make sure the kids have got toys, make sure they're not bored, and if they are, they do painting or bring a toy in," Emily says.

"The team always say to me, 'You can go out and get a coffee, go have a walk around, get some fresh air, I'm fine sitting here with Freya or Ricky'. They're really lovely."

With Freya and Ricky both having experienced periods of ill health and time in hospital, Emily is proudest of how they support each other. "Freya watched Ricky go through it all, and now she's not as scared," their mother says. 

Ricky reassures Freya when they are in hospital

"I know when they get older they can ask each other stuff. I know that Ricky will help out because he'll be the oldest, he knows about it a little bit but they will be so good for each other."

GOSH Charity exists to give seriously ill children the best chance and the best childhood possible, until no childhood is lost to serious illness. To find out more or to donate, visit gosh.Org/

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