Professors Muntoni and Bönneman and their teams have recently jointly published a paper (that the teams worked upon during lockdown) called “Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD”. It is published in Molecular Therapy: Nucleic Acids Vol. 21. You can view the original paper here.
In this study, they methodically assessed a number of antisense oligonucleotides (ASOs), also known as molecular patches, to see which ones worked best to correct a particular mutation (or mistake) in the COL6A1 gene. In this mutation, an extra exon is inserted into the gene – this is called a pseudo-exon. The pseudo-exon muddles up the gene and it cannot function properly. This mutation is one of the most common mutations in COL6A genes and found in several patients.
The teams designed fifteen ASOs and their effectiveness was evaluated using a number of techniques in skin cells from four patients carrying the mutation. Cells of patients grown under lab conditions make an excellent model to test the effectiveness of certain potential treatments such as molecular patches.
They identified some ASOs that efficiently stop the production of the pseudo-exon and allow for the creation of a functional matrix one normally sees with typical collagen VI.
The findings provide further evidence for ASO exon skipping as a therapeutic approach for COL6-CMD patients carrying this common mutation.
However, it is worth noting that the target cell population for treatment are cells called ‘interstitial fibroblasts’ that are found in skeletal muscle. These are the cells that make collagen VI. So far, the ASOs have been delivered under ‘laboratory settings’ and not in a way that would be comparable to how a treatment would be delivered to a patient. This requires further research.
Also, it is not clear whether putting collagen VI into skeletal muscle will bring back muscle function or only slow down disease progression. Nor do we know what the minimum levels correction need to be in order to provide a benefit for patients. This is known as a clinically meaningful therapeutic benefit.
Further studies on the effectiveness and safety in a suitable mouse model are needed before this approach can be eventually translated to clinical trials. These are currently being investigated by the research teams at the University College London and the National Institutes of Health in the United States.
Dr Haiyan Zhou, from University College London is one of the researchers supported by MDUK who co-authored the paper.
This is an important step forward in our understanding of how antisense therapy could be developed into a treatment for people with collagen VI-related myopathies. We are very grateful to the families that have donated funding to support our research, to the patients who so kindly donated their cells for research, and to the support from MDUK.