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What did the project achieve?
“We’re one step closer towards our goal of developing a new type of gene therapy for cystic fibrosis – the UK’s most common life-threatening inherited disease,” says Professor Stephen Hart at UCL Great Ormond Street Institute of Child Health. “While there is still a long way to go, the results from this project provide a strong basis for success that we can now continue to build from.”
Around 11,100 people in the UK, including more than 4,000 children, are living with cystic fibrosis.1 It is caused by a faulty gene, which leads to a disruption to the normal movement of salt and water in and out of cells – and a subsequent build-up of thick, sticky mucus in a child’s lungs and other organs. A child will experience a range of challenging symptoms that heavily impact their quality of life and can also shorten their life expectancy.
“In recent years, groundbreaking new treatments have been developed that can treat the underlying cause of cystic fibrosis – helping to reduce problems and make the condition easier to live with. But unfortunately, they don’t work for everyone – and around one in 10 children are still in desperate need of new treatments2,” says Professor Hart. “We’re aiming to develop a new type of gene therapy that can benefit all children with cystic fibrosis – so that no one is left behind.”
The new approach would involve delivering the correct version of the cystic fibrosis gene – in a form of the molecule called mRNA – into affected lung cells. The cell should then read these instructions to produce a healthy version of the faulty – or missing – protein, correcting the root cause of the disease. But the main challenge to developing this into a therapy is how to deliver the fragile mRNA molecules into the lung cells.
“To achieve this, we have developed nanoparticles that contain mRNA wrapped up in a mixture of protein and fat,” says Professor Hart. “After testing different formulations, we identified the most promising nanoparticles that best protect the mRNA, penetrate mucus, and deliver the mRNA into lung cells.”
The researchers then used these nanoparticles to deliver the mRNA into lung cells, grown in the laboratory from cells collected from patients with cystic fibrosis.
“Encouragingly, we showed that these lung cells started to make the correct cystic fibrosis protein and restored the normal movement of salt and fluids in and out of the cells,” says Professor Hart.
The team also showed that administrating the nanoparticles via inhalation from the back of the mouth was a safe and effective way to get mRNA into the lungs in a laboratory model.
“We hope that these nanoparticles can ultimately be developed into a new treatment for children with cystic fibrosis – particularly those who don’t benefit from the latest medicines,” says Professor Hart. “These children should not be forgotten – and we will not stop research until there are effective treatments available for everyone with the condition.”
References
1.Cystic Fibrosis Trust. UK Cystic Fibrosis Registry. 2022 Annual Data Report. Published September 2023. https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources [Website accessed 29 January 2024]
2. Kramer-Golinkoff et al. A survey: Understanding the health and perspectives of people with CF not benefiting from CTFR modulators. 2022; 57(5): 1253-1261.
This research was completed on
Around 10,400 people in the UK, including more than 4,000 children, are living with cystic fibrosis.1 It is an inherited condition, with a range of symptoms caused by a build-up of thick sticky mucus and affecting many organs. Sadly, two people with cystic fibrosis will lose their lives every week, with lung damage due to regular chest infections a big factor.2 Professor Stephen Hart at UCL Great Ormond Street Institute of Child Health is aiming to develop a new type of gene therapy that can restore normal function in affected lung cells. He hopes that this work will one day benefit children and adults with cystic fibrosis – helping them to live longer, healthier lives.
Action Medical Research and the Cystic Fibrosis Trust are together funding this study
How are children’s lives affected now?
Cystic fibrosis is the UK’s most common life-threatening inherited disease. It is caused by a faulty gene, which leads to a disruption to the normal movement of salt and water in and out of cells – and a subsequent build-up of thick, sticky mucus in a child’s lungs and other organs.
Children with the condition experience a range of challenging symptoms that heavily impact on their quality of life. Their lungs are particularly affected, and over time the mucus can block and damage their airways, leading to repeated infections and making it hard to breathe.
“Symptoms usually start in early childhood and get slowly worse, with their lungs becoming increasingly damaged – and this can be fatal if it leads to a serious infection or they stop working properly,” says Professor Hart.
Although there is no cure, treatments are available that can help to reduce problems and make the condition easier to live with. But sadly, a child born with cystic fibrosis will have a shortened life expectancy.
How could this research help?
“Our goal is to develop a new gene therapy that can restore the normal movement of salt and fluids in lung cells, correcting the mucus problem in children with cystic fibrosis,” says Professor Hart.
The team will first perform test-tube experiments to identify the most stable, efficient version of the cystic fibrosis gene - in a form of the molecule called mRNA.
“We will then wrap the cystic fibrosis mRNAs in a mixture of protein and fat called a nanoparticle, which we hope will protect and carry it through the mucus and into the lung cells,” explains Professor Hart.
The researchers will then perform a series of laboratory experiments to assess the potential of the nanoparticles at correcting the problems caused by the faulty gene in cells and living systems.
“We hope that our laboratory work will lay the foundations for a new inhaled gene therapy that can one day dramatically improve the lives of children born with cystic fibrosis,” says Professor Hart.
References
1.Cystic Fibrosis Trust. UK Cystic Fibrosis Registry. 2017 Annual Data Report. Published August 2018. https://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources [Website accessed 25 September 2018]
2.British Lung Foundation. Cystic Fibrosis statistics: https://statistics.blf.org.uk/cystic-fibrosis [Website accessed 25 September 2018]
| Project Leader | Professor Stephen L Hart, PhD |
| Project Team | Professor Chris O’Callaghan, BM BS MRCP FRCP DM FRCPCH PhD FSB, Professor Robin J McAnulty, PhD |
| Project Location | Department of Experimental and Personalised Medicines, UCL Great Ormond Street Institute of Child Health |
| Project Location Other | Department of Respiratory, Critical Care & Anaesthesia, UCL Great Ormond Street, Institute of Child Health, UCL Respiratory, Centre for Inflammation and Tissue Repair, University College London |
| Project duration | 2 years |
| Date awarded | 19 September 2018 |
| Project start date | 1 October 2018 |
| Project end date | 31 July 2021 |
| Grant amount | £154,634 |
| Grant code | GN2734 |
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