PCD Research is co-funding a 2 year research project with NATA
Developing future treatments for CCDC39
This research looks to develop potential future mRNA treatments. We have started by commissioning research to look specifically at the gene CCDC39 as this is the 3rd most common disease causing gene, and is associated with one of the most severe outcomes. This has the potential to be used as a proof of concept to address other genotypes in the future. This research is in progress at University College London, led by Professor Steven Hart and is undertaken by Dr Eriomina Shahaj.
Summary of planned research
- Bronchial or nasal samples taken from a patient with PCD caused by loss of function of CCDC39.
- mRNA for CCDC39 prepared – these are guide templates to make a CCDC39 protein.
- Patient cells are grown in culture to make an air liquid interface culture (ALI) that is a laboratory model to study lung disease. The prepared mRNA is dropped onto these cells to see if it is possible to restore cilia motility. This process is outlined in the second figure.
- Characterisation of the mRNA and fatty coating (lipid nanoparticle) to understand if it is possible to get to the lungs with being damaged and breaking down.
How air-liquid interface cultures are made and used
- Patient cells are collected from nose or lungs
- These cells are grown in the laboratory
- These cells are modified so that the grow for longer outside of the body.
- This is done by turning on a gene so that a protein called BMI1 is always expressed.
- These cells can then survive for much longer (immortalised).
- The cells are then moved into a plastic well and covered with growth media (liquid food).
- TEER is measured to check whether the cells have joined together to form a proper layer, like they do in the body, so we know the model is working as it should.
- This is now an air-liquid interface (ALI) culture that can be used to study lung disease.
- CCDC39 mRNA (template for CCDC39 protein) in a fatty coat (lipid nanoparticle).
- mRNA added to the ALI culture.
- Aim to restore ciliary function in the ALI culture.
Dr Eriomina Shahaj has presented her work so far at a number of conferences:
- Gordon Research Seminar: Cilia, Mucus and Mucociliary Interactions.
- LifeArc Rare Respiratory Centre update meeting.
- PCD Foundation: On the Move (Prize Winner)
What is next?
After this research project, more will be needed before a clinical trial in humans to further define:
- Nature of restoration of ciliary function.
- Delivery to the lungs.
- Effectiveness of the mRNA treatment in a mouse model of disease.
- Dosing amount and treatment interval.
- Safety profile.