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Drug repurposing – are we making progress in EB?

Drug repurposing – are we making progress in EB?

Recently DEBRA UK funded a project with Professor Jouni Uitto at the Thomas Jefferson University in Philadelphia, USA to look at novel approaches for “read through of nonsense mutations” in COL7A1. The summary for this project can be found here.

Professor Uitto and his group have recently published a very encouraging clinical paper on their findings. The paper has been published in the Journal of Investigative Dermatology. The paper is entitled “Amlexanox enhances premature termination codon read-through in COL7A1 and expression of full-length type VII collagen: potential therapy for recessive dystrophic epidermolysis bullosa” by Atanasova and colleagues.

A family of proteins, the collagens, are responsible for the structural integrity of skin. In recessive dystrophic epidermolysis bullosa (RDEB) there is a fault in an important collagen, type VII, that means the outer epidermis of the skin cannot anchor properly to the underlying dermis, resulting in fragile skin that damages and blisters very easily, giving rise to wounds that heal poorly with excessive scarring.

This fault is caused by a mutation (or mistake) in the gene (COL7A1) that controls the manufacture of collagen VII. Genes work by providing a ‘code’ that is ‘read’ by the molecules inside the skin cells responsible for synthesising the protein. These molecules use the information in the code to ensure that the protein they make has the right components and that they are assembled correctly. In DEB, the mistake in the gene causes the protein synthesis mechanism to stop prematurely – resulting in a collagen VII molecule that is too short to function properly. About 46% of RDEB patients have this gene mutation.

While significant advances have been made in treatment for RDEB, they are often associated with long and expensive procedures and some have serious side effects. This group, however, have been looking at a different approach, using a compound that causes the ‘stop’ signal in the gene to be ignored or ‘read through’ and so allowing the cell machinery to go on to make complete full-length collagen VII molecules, despite the mutation in the gene. There have been previous studies showing that compounds do exist that can cause ‘read through’ but the most common of these, gentamycin, is too toxic to have clinical application.  This new compound, amlexanox, has already been approved by the US regulatory authorities (the FDA or Food and Drug Administration) for treating mouth ulcers and is being investigated in type 2 diabetes so we know that it can be given orally with no adverse effects reported.

Two types of skin cells involved in collagen VII production, called fibroblasts and keratinocytes, that had mutated COL7A1 genes were taken from RDEB patients. They had different mutations, but all having the same effect of stopping the synthesis of collagen VII prematurely. The cells were treated in the laboratory with amlexanox. The treated cells were able to produce full length collagen VII in two thirds of cases. The fact that some did not respond is not a negative finding; it shows that some mutations can be overcome this way, but others cannot, so the treatment can be given just to those patients who stand to benefit. It was found that patients who were naturally producing a small amount of full-length collagen VII, albeit at considerably lower levels than normal, responded best. The collagen VII produced after amlexanox treatment was fully functional and found at the dermal-epidermal junction in cell cultures.

This study also compared amlexanox with gentamycin and showed greater success for the amlexanox without the toxicity seen with gentamycin. Thus, this study has shown the potential for developing this ‘read through’ promoter amlexanox as a treatment for RDEB. It might not benefit all RDEB patients, but can be focused on those who will respond.

This work may be applicable for patient treatment in the future, the group are currently looking into the possibility of a small patient study to see if the results translate into similar success in the clinic.

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