Bespoke antisense oligomer-mediated splice modulating therapies for recessive dystrophic epidermolysis bullosa patients
Lay summary
Recessive dystrophic epidermolysis bullosa (RDEB) is caused by a fault in COL7A1, the gene responsible for making collagen 7, which acts like the glue that holds the skin layers together. In people with RDEB, this gene does not work correctly, leading to very little or no collagen 7, and their skin becomes fragile and prone to painful blistering.
Although different gene defects are reported for the collagen 7 gene, many defects result in greatly reduced production of collagen 7 through a common mechanism of premature termination of the gene message. Using an emerging class of drugs known as antisense oligomers, we will design drugs to allow the cells to skip over the disease-causing part of the gene message, thereby allowing some collagen 7 production to resume. This “skipping” process occurs naturally but at very low levels, typically too low to be clinically significant. However, this personalised medicine approach will be tailored to greatly enhance any natural skipping to remove the faults in the collagen 7 gene message.
Although we will need to design and test each antisense drug for each defect, collagen 7 production will only resume where needed, as our drug should only work in cells where collagen 7 is made. Patients will require ongoing treatment since we are not fixing the gene defect; the new therapy will override the genetic defect to enable collagen 7 production. Since no stable genetic changes in patient DNA will be attempted, this is expected to be a safer approach than other gene therapies.
Scientific Summary
This study endeavours to develop personalised antisense oligomer-mediated splice-modulating therapies for individuals diagnosed with RDEB. We aim to enlist twelve patients and develop customised antisense therapies to restore collagen 7 protein expression in patient-derived cells.
We will use RNA and protein analysis to identify each patient’s most amenable mutation to design the most promising antisense therapeutic to mitigate disease progression. Subsequently, we will assess the efficacy of the lead candidate(s) initially in an in vitro organotypic engineered skin model, followed by in vivo confirmation using patient cell-derived skin-grafted mice.