Chemical suppressors of nonsense mutations for the treatment of frontotemporal dementia
University of British Columbia
The principal role of the human genome is to produce proteins that serve as building blocks for all aspects of the body, including the brain. During protein production, a stop signal contained within a single gene ensures that the process ends when the protein is completed.
Sometimes this stop signal occurs prematurely due to a genetic mutation. Such premature stop signals typically result in nonfunctional or absent protein, which in turn can cause disease. A relatively recent discovery indicates that one such genetic mutation in a gene called progranulin (GRN) can cause a type of dementia called frontotemporal dementia (FTD). In patients younger than 60, FTD is the second most common cause of dementia, manifesting as progressive behavioral impairments and dementia typically starting in the 6th decade. We have discovered a set of novel therapeutic compounds which is able to “ignore” a premature stop signal, and thus produce a normal protein even when affected by a mutation. In this project we will test these novel compounds directly in cells derived from patients with FTD and the relevant genetic mutation. We will also test the drug combinations in a rodent model of the disease. A successful project will allow for future human trials, and possibly an effective treatment for some forms of FTD.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Patients with a pathologic mutation in progranulin produce about 50% less of this protein. There is a clearly established link between this mutation and frontotemporal dementia, and restoring function, by bypassing the relevant mutation, could be a highly effective therapy. We are testing drug combinations that are likely to be easily translated to human disease, and a successful preclinical project would allow for direct extension of the study to human subjects.
The goal of this project is to establish that our compound combination successfully restores production of the protein progranulin (GRN), in the setting of a genetic mutation which would typically reduce such production by 50% and lead to dementia (frontotemporal dementia – FTD). Restoration of progranulin production may be a critical step towards a cure for this type of FTD. We will show that our compounds restore progranulin in a cell line derived directly from patients, and in a mouse model with the equivalent human mutation inserted into its genome. The results from these models will be translated to human disease, with a successful outcome leading to human clinical trials.