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What did the project achieve?
Some babies are born with severe breathing difficulties and require immediate mechanical ventilation in intensive care, with a poor chance of survival. In rare cases, these problems are caused by changes in the ABCA3 gene, which provides the instructions for making a protein needed to produce surfactant – a substance that helps the lungs stay open during breathing. Without normal surfactant, the lungs can collapse, leading to life-threatening breathing difficulties.
“Our laboratory findings are encouraging, bringing us a step closer towards testing this new gene therapy in early-stage clinical trials,” says Professor Deborah Gill of the University of Oxford. “Ultimately, if this treatment is successful, we hope it will enable the baby’s lungs to produce normal surfactant, helping them to breathe independently.”
The researchers are developing a gene therapy that delivers a working copy of the ABCA3 gene directly into lung cells, enabling them to make functional ABCA3 protein and addressing the underlying cause of the disease.
“We have successfully developed a new method for delivering genes to the lungs using a harmless virus,” says Professor Gill. “Using laboratory models of the disease, we have tested key aspects of this gene therapy and shown that it can function in the lung cells where it is needed.”
The researchers had originally planned to use an existing laboratory model of the disease, but it proved unreliable. Instead, they developed new models of ABCA3-deficiency using human lung cells.
“Using these advanced cell models, we showed that our gene therapy could correct several features of the disease,” says Professor Gill. “We have now carried out initial safety studies on the most promising version of the treatment, which we now hope to advance to the next stage of development.”
The next step is to submit the results of these studies to the relevant authorities to seek permission to take this potential new treatment forward into clinical trials.
This research was completed on
This project is jointly funded by Action Medical Research and LifeArc.
How are children’s lives affected now?
Lung surfactant is a complex mixture of fats and proteins that lines the lung tissue and makes breathing easy. Without normal surfactant, the lungs can collapse, leading to life-threatening breathing difficulties.
“Sometimes babies are born with very severe breathing difficulties that don’t respond to the usual treatments,” says Professor Gill. “They will need to be placed on a ventilator in intensive care – and sadly, their chances of survival are very poor.”
Research has identified faults in several genes that can cause lung surfactant deficiency – including ABCA3, which provides the instructions for making a protein involved in surfactant production. Faults in this gene can cause life-threatening breathing difficulties in newborn babies or milder symptoms in older children.
“Treatment options are limited for babies born with severe lung surfactant deficiency caused by faulty genes such as ABCA3,” says Professor Gill. “New life-saving therapies are desperately needed to provide hope for children and their families affected by this rare disease.”
How could this research help?
“Our goal is to develop a new gene therapy for babies with severe breathing problems caused by faults in the ABCA3 gene,” says Professor Gill.
The researchers plan to use a harmless virus to deliver a working copy of the ABCA3 gene into the baby’s lung cells. By enabling babies to make normal lung surfactant, this treatment should help them to breathe without mechanical ventilation.
“We will first carry out experiments to test the effectiveness of the approach in human cells and in a laboratory model of ABCA3-deficiency,” says Professor Gill. “Our results will indicate whether this gene therapy is likely to help babies with this rare and devastating condition.”
The next step would be to set up a clinical trial to test the safety and effectiveness of delivering the treatment directly into babies’ lungs through the ventilator breathing tube.
If successful, this gene therapy could transform the outlook for babies born with severe lung surfactant deficiency. It could also provide benefits for children with milder symptoms of the disease.
References
- Kröner, C. et al. Lung disease caused by ABCA3 mutations. Thorax 2017; 72(3):213-220.
Research table
Project details
| Project Leader | Professor Deborah R Gill, PhD |
| Location | Radcliffe Department of Medicine, Nuffield Division of Clinical Laboratory Sciences, University of Oxford |
| Project Team | Professor Stephen C Hyde, DPhil |
| Grant Awarded | |
| Grant Amount | £271,474 |
| Start Date | |
| End Date | |
| Duration | 30 months |
| Grant Code (GN number) | GN2929 |
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