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Investigating molecular patch approaches for a COL6A1 variant

Professor Carsten Bonnemann and his colleagues from the National Institute of Health (US) aim to develop a new kind of exon-skipping therapy for Collagen VI-related muscular dystrophy that can be delivered using adeno-associated virus (AAV).
Principal Investigator
Professor Carsten Bonnemann
National Institute of Health
Official title
COL6A1 intron 11 pseudo-exon skipping using scAAV-delivered U7snRNA-driven splice modulation
24 months
Total cost
Congenital muscular dystrophy


Collagen VI proteins sit outside muscle cells and are part of a protective and support environment called the extracellular matrix. If collagen VI is altered in some way, perhaps because of genetic changes in one of the collagen VI genes, COL6A1, COL6A2 or COL6A3, then the environment outside of the cells provides less support and is less protective. This can lead to muscle damage and can cause congenital muscular dystrophies such as Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD).

Professor Bonnemann and his team have identified a genetic change in COL6A1, called the COL6A1 c.930+189C>T variant, that leads to the addition of an extra piece of genetic sequence to the COL6A1 RNA, also known as a pseudoexon. This genetic change causes damage to the extracellular matrix – a network of proteins and other molecules outside the cells that give support, structure, and help the cells communicate with each other – leading to a severe form of COL6-related muscular dystrophy.

What are the aims of the project?

This project aims to develop a specific kind of molecular patch for exon-skipping therapy, calling it ‘pseudoexon-skipping’, to target the above-mentioned genetic change. Once Professor Bonnemann’s team has identified a promising molecular patch, it will be packaged into a viral vector and tested in a mouse that has a similar genetic change to ensure the technology works in real muscle.

Why is this research important?

The COL6A1 c.930+189C>T variant causes a severe type of collagen VI-related muscular dystrophy. Finding a way to reduce the severity of its progression by skipping the pseudoexon could have a beneficial effect on people living with Bethlem myopathy and UCMD. If this project shows positive results, the potential therapy will move to larger animal studies before going to clinical trials.

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