Cystic fibrosis is caused by a genetic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In one class of mutation, the CFTR is stopped from being produced because stop codons, signals to end the production of the protein at a particular point, occur prematurely. The Trust is funding a project led by Professor Floto at Cambridge University to research the use of stem cells to correct the gene and so allow CFTR to be produced.
The research team aims to:
- Generate Induced Pluripotent Stem Cells (IPSCs) from the white blood cells of individuals with cystic fibrosis (CF) who have one copy of one of two rare premature stop codon mutations (W1282X or G542X) in the CFTR gene.
- Use a special gene editing technique called ‘CRISPR-mediated genome editing’ to correct this mutation and permit expression of full- length, functional CFTR.
- Grow and develop (differentiate) the IPSCs into epithelial (lung airway) cells and evaluate the functional consequences of gene correction.
This project represents the first step in developing genome editing as therapy in cystic fibrosis and will provide a model system to test new drugs for CF (such as ataluren derivatives) in the lab.
Mutations in the CFTR protein, such as W1282X and G542X, cause the messenger RNA, a strand of genetic code for the protein, to have premature stop codons. This means that the CFTR protein that is being coded for is not produced in a complete form due to the stop codon halting the chain of amino acids before the protein production is complete. People with cystic fibrosis who have these mutations therefore have a non-functional CFTR.
For the CFTR protein to be functional it must be complete, so to target this problem it is necessary to prevent the stop codon appearing prematurely in the production sequence. If this can be corrected by gene editing it could offer a potential form of gene therapy for people with cystic fibrosis.
Induced Pluripotent Stem Cells (IPSCs) have a unique ability to differentiate into numerous types of body cells. This means stems cells can be generated from people who have cystic fibrosis and have at least one copy of the mutation. Once they have been generated genome editing can then be used to correct the defect before growing the cells into lung cells.