Gentamicin B1 as treatment for Rare Genetic Diseases
More than 7000 rare genetic diseases affect over one million Canadians. Most have no treatment and many patients die in childhood. The small number of patients for each disease makes it difficult to develop treatments. About 10% of cases are due to a nonsense mutation that creates a premature termination codon (PTC) so the protein produced is cut short at the mutation and cannot function. A potential therapy is PTC readthrough in which a small molecule allows incorporation of an amino acid at the PTC, allowing the rest of the protein to be formed and function to be restored. PTC readthrough therefore is mutation-specific rather than gene-specific or disease-specific and has the potential to treat many different rare diseases. Drugs that induce therapeutic levels of PTC readthrough at safe doses are not yet available.
The effort to find just such a drug led to the innovation that won Dr. Roberge a place among the inaugural cohort of winners of the Michael Smith Foundation for Health Research’s Innovation to Commercialization (I2C) award. The I2C Program is designed to help researchers advance discoveries or inventions towards commercialization by supporting commercialization activities that strengthen the value of their intellectual property, facilitate collaboration and attract future investment.
Dr. Roberge has discovered that Gentamicin B1 (B1) potently induces PTC readthrough in cultured cells from patients with different rare diseases, making it a promising drug candidate. Dr. Roberge and colleagues published this innovative finding in the prestigious journal Proceedings of the National Academy of Sciences in March 2017. (Click here to read publication)
The I2C award, will support Dr. Roberge and his team in taking Gentamicin B1 through the next stage of drug development. Specifically they will test it in cell and animal models of a rare genetic disease to see if it induces enough normal protein to correct the defect without toxic side effects.
For these proof-of-principle studies they will focus on nonsense mutations causing epidermolysis bullosa. Epidermolysis bullosa is a set of devastating, often fatal, skin fragility diseases resulting from mutations in genes encoding structural proteins that anchor together the epidermis and dermis; even minor friction causes painful blisters and wounds that can lead to severe deformities and skin cancer. Current treatments are palliative only and focus on management of pain and infection.
For this work, Dr. Roberge has established collaborations with clinicians and researchers specializing in epidermolysis bullosa to create a collection of cells from patients. Dr. Roberge’s team will first make human skin equivalents from patient epidermal and dermal cells, treat them with B1, and measure full-length protein production and restoration of adhesion between epidermis and dermis. Then, B1 will be tested in an animal model where the skin equivalent will be transplanted to an immuno-deficient mouse and the mouse will be treated with B1 either systemically by injection or topically in a cream, before making measurements of full protein and adhesion restoration.
Results from this study will not only help Dr. Roberge’s team move one step closer to an unprecedented treatment for epidermolysis bullosa, but also pave the way for further research into the use of Gentamicin B1 as a treatment for several other rare genetic disorders.