Grant: Proof of Principle Program - Phase I

Many genes that cause cancer or rare genetic diseases have a mutation that creates a stop signal within the gene instead of only at the end. The protein made from that gene is therefore truncated at the mutation and cannot function properly, resulting in disease. Treatments that enable cells to ignore the premature stop signal and produce full-length protein, a process called premature termination codon (PTC) readthrough, can restore normal function and prevent disease progression. The antibiotic gentamicin can induce PTC readthrough but only at high doses that can also cause kidney toxicity and deafness. Gentamicin is not a pure drug but a mixture of several similar chemicals. Dr Roberge's group has discovered that a gentamicin analog, a minor component, is responsible for the PTC readthrough activity of gentamicin and the remaining >95% of the chemicals are inactive. In cell culture experiments, the gentamicin analog induces much more PTC readthrough than gentamicin, and at doses 100-fold lower. This raises the exciting possibility that the gentamicin analog could induce significant readthrough in humans at doses that are not toxic to the kidneys or ears. Although the gentamicin analog is a component of a drug approved for use in humans, it is not itself an approved drug. Therefore, experiments in animal models must first be carried out to demonstrate its efficacy and safety before it can be tested in humans. The goal of this proposal is to carry out experiments using mice to determine whether short and longer-term treatments with the gentamicin analog can induce substantial PTC readthrough without affecting the kidney or ears. These experiments will provide key proof of principle data about the therapeutic potential of the gentamicin analog to treat patients with a rare genetic disease or a cancer arising from a PTC mutation. A successful outcome will enhance the patent position and support the creation of a start-up company devoted to taking the gentamicin analog into clinical trials.