What did the project achieve?
“The preliminary results from our laboratory experiments show that two drugs may help to ‘read through’ the genetic defect in a rare and severe form of primary ciliary dyskinesia,” says Professor Chris O’Callaghan of the UCL Great Ormond Street Institute of Child Health. “Although it’s still very early days, it suggests that this exciting new treatment approach could one day benefit children with this debilitating condition.”
Lining the surface of our nose and airways are millions of microscopic hairs called cilia that are constantly beating. Working together, these tiny structures continually clear away mucus and debris, helping to prevent infection and lung damage.
Primary Ciliary Dyskinesia (PCD) is a rare inherited condition where defects in these hair-like structures affect how they beat. This leads to a build-up of mucus that causes symptoms that include a persistent cough and recurrent chest infections that can greatly reduce a child’s quality of life and can lead to permanent lung damage.
This research involved using cells from children with a particularly severe type of PCD grown in the laboratory. The team tested the effects of two drugs with the potential to ‘override’ certain gene faults and correct ciliary function.
“After adding these drugs, the cells started making the missing building block that cilia need to grow, and to form the ‘root’ of this structure,” says Professor O’Callaghan. “While these results are encouraging, the next step will be to see if the approach will enable the regrowth of cilia that are absent in this form of PCD.”
The team also developed a new system that allows huge numbers of cells to be grown from patients with rare forms of PCD that can now be used to accelerate research. In collaboration with others, they also worked on a new formulation for one of the drugs that markedly improved its ability to get into target cells.
“We hope this could eventually lead to a way to deliver it directly into a child’s lungs, helping to reduce the risk of side-effects during long-term treatment,” says Professor O’Callaghan.
This research was completed on
Children with a debilitating, inherited illness called primary ciliary dyskinesia (PCD) may one day benefit from research by Professor Chris O’Callaghan and colleagues, of University College London and Great Ormond Street Hospital. Children with this rare condition have a persistent cough from birth and face a lifetime of recurrent chest infections. They often develop hearing loss and eventually permanent lung damage. Treatment with antibiotics and daily physiotherapy to clear mucus from the lungs helps, but there’s no cure. Professor O’Callaghan is investigating a possible new approach to treatment, in the hope of tackling the cause of children’s symptoms and improving their lives.
How are children’s lives affected now?
“Babies and children with PCD have a persistent, wet-sounding cough, which never goes away, and a constantly runny or partially blocked nose,” says Professor O’Callaghan. “Symptoms continue daily and are lifelong.”
“Exercise, coughing and physiotherapy sessions – which children need a number of times a day – help by removing some of the mucus from children’s lungs,” continues Professor O’Callaghan. “Unfortunately, though, many children develop long-term chest infections, which can cause progressive – and permanent – lung damage. Over half of children with PCD also have hearing problems, meaning they need hearing aids.”
Long-term infections require treatment with multiple courses of antibiotics, with children sometimes needing to stay in hospital. Very badly affected children may eventually require lung transplantation.
“Records from clinics in the UK suggest around 90 children are diagnosed with PCD here each year,” says Professor O’Callaghan.1 “Worryingly there’s a lack of evidence on the best way to treat them and no cure.” Research into better treatment is needed urgently.
How could this research help?
The team’s ultimate goal is to develop a new treatment for PCD that corrects the underlying cause of children’s symptoms – faults in tiny hair-like structures called cilia that line the surface of the airways.
“We believe four out of every 10 children with PCD in the UK have what we call a nonsense mutation in their DNA,” says Professor O’Callaghan.2 These mutations, or changes, stop children’s cilia from working normally – the cilia don’t sweep mucus or infectious agents, such as bacteria, out of the lungs properly.
“Evidence suggests a number of drugs can help overcome problems caused by nonsense mutations,” continues Professor O’Callaghan. “We’re studying two of these drugs in the laboratory to see if they can correct defects in cilia on cells taken from children with PCD. This will require a lot of research.”
“If the drugs we’re testing show promise in the laboratory, clinical trials could follow quickly in children with PCD, because there’s already good evidence to support their safety in humans,” says Professor O’Callaghan. “Drugs that can restore the ability of cilia to work properly could help children move mucus out of their lungs, which would hopefully improve their health.”
1. Personal communication with Professor O’Callaghan, based on audit figures from PCD national diagnostic service.
2. Personal communication between Professor O’Callaghan and Dr Hannah Mitchison of University College London’s Institute of Child Health.
|Professor Chris L O'Callaghan BMedSci FRCPCH, FRCP, FSB, DM, PhD
|Professor Philip Beales FMedSci FRCP MD MRCPUK MRCS LRCPDr Hannah Mitchison BSc PhDDr Elizabeth Forsythe MRCPH MBBS BMedSciProfessor Steve Hart PhD MSc BScDr Claire Smith PhD BScDr Rob A Hirst PhD BSc
|Respiratory, Critical Care & Anasesthesia, Institute of Child Health, University College London, and Great Ormond Street Hospital
|Project Location Other
|Genetics and Genomic Medicine Programme, Institute of Child Health, University College LondonMolecular Immunology Unit, Institute of Child Health, University College LondonRespiratory, Critical Care and Anaesthesia Section, Institute of Child Health, University College LondonCentre for PCD Diagnosis and Research, University of Leicester
|21 November 2014
|Project start date
|1 March 2015
|Project end date
|1 September 2018
|This project is supported by a generous grant from The Henry Smith Charity