MDUK-funded researchers have corrected a common mutation causing Ullrich congenital muscular dystrophy (UCMD) using two genetic tools. Although these experiments were carried out in cells in the laboratory, further research could lead to the development of a potential treatment for UCMD.
Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in genes that produce collagen VI protein. This protein forms networks around our muscle cells and acts as a scaffold to hold and support them. In someone with UCMD, the collagen scaffold is faulty or absent, which means that their muscle cells are not supported properly and become damaged over time.
This new study from Prof Carsten Bonnemann (NIH, US), Prof Francesco Muntoni (University College London) and others focussed on a recently identified mutation in the COL6A1 gene. This mutation creates an extra, unwanted exon in the gene. It appears to be one of the most common mutations so far identified in COL6A genes, and is thought to be a common cause of UCMD.
The researchers wanted to test whether removing this unwanted exon could restore the function of the collagen VI protein in cells taken from UCMD patients. They did this using two genetic techniques: exon skipping and genome editing.
As the name suggests, the principle of exon skipping is to encourage the cellular machinery to ‘skip over’ an exon. Small pieces of DNA or RNA, called antisense oligonucleotides or ‘molecular patches’, are used to mask the exon so that it is ignored during protein production.
Genome editing is a technique that allows scientists to change a gene at the DNA level. It uses molecular scissors to make precise cuts in the DNA, which are then repaired naturally by the cell.
In this study, the researchers designed molecular patches and molecular scissors that target the unwanted exon in the COL6A1 gene (see below). They found that both strategies successfully removed the exon from the gene message, resulting in improved assembly of the collagen VI scaffold outside the cells.
We’re continuing to support the research of Professor Bonnemann and Professor Muntoni, who are now working towards testing the molecular patch in a relevant mouse model. Professor Muntoni and his team at the University College London are also developing molecular patches for other COL6 mutations.
The study was published in the scientific journal, JCI Insight.