Muscular Dystrophy Campaign funded research at Newcastle University has investigated whether the drug Cyclosporine A could be used to treat Bethlem myopathy and Ullrich congenital muscular dystrophy (CMD).
- Background information
- What does the new research show?
- What does this mean for patients with BM & UCMD?
- Further Information and links
Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD) are disorders that are known to be caused by mutations in the genes that code for a protein called collagen VI. Collagen VI is located on the outside of the cell as part of a complex mixture of other proteins and sugars; this is called the extracellular matrix or ECM. The extracellular matrix provides structural support to the cell as well as performing various other important functions such as sticking cells together and mediating communication between cells.
Previously researchers in Italy reported another surprising effect of the collagen VI mutation in a mouse model and in BM and UDMD patient cells grown in the laboratory. The “mitochondria” were found to be dysfunctional. Mitochondria are the batteries of cells, providing them with energy. It was thought abnormal collagen VI protein could cause dysfunction of a specific type of pore on the surface of the mitochondria. Abnormally functioning pores on the mitochondrial surfaces can lead to the death of muscle cells.
They proposed that the drug cyclosporine A could be used to treat individuals with BM and UCMD. Cyclosporine A is known to act by inhibiting the opening of the pores on the surface of the mitochondria. You can read more about this research here.
Kate Bushby’s group in Newcastle set out to further investigate the possibility of cyclosporine A treatment for individuals with BM and UCMD. They looked at the mitochondrial function in cells from patients with UCMD and BM as well as those with other muscle diseases including Duchenne muscular dystrophy, limb girdle muscular dystrophy (LGMD) and congenital muscular dystrophy.
The results of their study showed that the link between collagen VI mutation and mitochondrial dysfunction is not conclusive. They did not find mitochondrial dysfunction in cells from UCMD patients which are known to produce most of the collagen IV in the muscle (the fibroblasts). Additionally, mitochondrial dysfunction was not found in muscle cells from patients with other muscle diseases where it would be expected because these cells are known to be susceptible to cell death.
The only cells that did have mitochondrial dysfunction were muscle cells (myoblasts) from UCMD patients and those from a LGMD2B patient. These cells have in common that they do not grow well in the laboratory and the researchers suggest that the reason for the apparent mitochondrial dysfunction in these cells is due to the ill health of these cells, rather than a direct consequence of the gene mutation. They also found that the mitochondrial dysfunction in these cells could be corrected by agents unrelated to cyclosporine A which indicates that this drug might not be specifically treating the cells.
It is essential that future investigations aim to better understand the pathway linking the genetic mutation in UCMD and BM to the onset of symptoms. This will allow drugs that specifically target the process causing the muscle disease to be investigated.
The full original paper is available by subscription only. The article is written in technical language with no summary in layman’s terms. The reference for the paper is:
Hicks D, Lampe AK, Laval SH, Allamand V, Jimenez-Mallebrera C, Walter MC, Muntoni F, Quijano-Roy S, Richard P, Straub V, Lochmüller H, Bushby KM. Cyclosporine A treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue. Brain. 2009 Jan;132:147-55.2008 Nov 16.