Professor Carsten Bönnemann and his team at the National Institute of Neurological Disorders and Stroke in Maryland, NIH USA, will make a new mouse model with Ullrich congenital muscular dystrophy (UCMD), which will be an important tool for researchers. They will use this to test a molecular patch that could be a potential treatment for people with UCMD.
What are the aims of the project?
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, it is faulty or absent, which means that their muscle cells are not supported properly and become damaged over time.
Professor Bönnemann and his team recently identified a new mutation in the COL6A1 gene, which is now thought to be one of the most common causes of UCMD. The primary aim of this project is to generate a mouse model with this mutation. The researchers will carefully examine the mice to see if they have similar symptoms to people with UCMD. This will help to determine their usefulness as a model for testing potential treatments.
This particular mutation creates an extra, unwanted exon in the COL6A1 gene. The unwanted exon could potentially be excluded using a therapeutic approach called exon skipping.
The researchers will test the exon skipping approach in the new UCMD mouse model. This involves injecting the mice with synthetic pieces of DNA called molecular patches, which instruct the collagen VI-producing cells to ignore or ‘skip’ the extra COL6A1 exon. This aims to restore the production of collagen VI protein in the mice and stabilise or at least slow down the progression of the condition.
Designing the specific molecular patch will be carried out in collaboration with Professor Francesco Muntoni and his team at University College London. They are currently developing molecular patches targeting several UCMD mutations (read more about Prof Muntoni’s project).
Why is this research important?
Scientists need models in order to understand the underlying biology of a condition, or the effect of a potential treatment. This project will generate the first animal model with this particular COL6A1 mutation, which will be a valuable research tool for the UCMD field.
How will the outcomes of this research benefit people with UCMD?
This project will test the feasibility and effectiveness of a molecular patch treatment in a mouse model of UCMD. This preclinical research is essential for new drugs or treatments to be able to advance to human clinical trials.
How might this research impact on other neuromuscular conditions?
The knowledge gained from this project could help to enhance molecular patch technology generally. This could be beneficial for several muscle-wasting conditions for which molecular patches are being developed, including Duchenne muscular dystrophy, spinal muscular atrophy, facioscapulohumeral muscular dystrophy and myotonic dystrophy.
Project leader: Professor Carsten Bönnemann
Institute: NIH National Institute of Neurological Disorders & Stroke, Maryland, USA
Condition: Ullrich congenital muscular dystrophy
Duration: Two years
Total cost (£): 67,617
Official title: A humanized mouse model of COL6RD to test exon-skipping therapeutics against a pseudo-exon inclusion