More than 5,000 rare genetic diseases affect over one million Canadians. Most have no treatment and many patients die in childhood. The small number of patients each of these diseases affects makes it difficult to develop treatments. However, about 10% of cases are due to a nonsense mutation that creates a premature termination codon (PTC); the protein produced is consequently cut short at the mutation and cannot function.
A potential therapy for this phenomenon is called ‘PTC readthrough,’ which allows the rest of the protein to form, restoring its function. As PTC readthrough is mutation-specific rather than gene-specific or disease-specific, it has the potential to treat many different rare diseases. However, drugs that induce therapeutic levels of PTC readthrough at safe doses are not yet available.
Dr. Roberge’s research has uncovered that gentamicin B1 (B1) potently induces PTC readthrough in tissue culture cells from patients with different rare diseases, making it a promising drug candidate. His lab will take B1 through the next stage of drug development—efficacy testing in cell and animal models—to see if it induces enough normal protein to correct the defect without toxic side effects. For these proof-of-principle studies he will focus on nonsense mutations causing epidermolysis bullosa (EB), a set of devastating, often fatal, skin fragility diseases.
Dr. Roberge has established collaborations with clinicians and researchers specializing in EB to create a collection of patient cells, from which human skin equivalents can be made, treated with B1, and their full-length protein production measured. A successful outcome would justify the activation of a start-up company in British Columbia to develop B1 towards the clinic, potentially working towards improved patient outcomes for many rare diseases.