Chemical suppression of nonsense mutations for the treatment of frontotemporal dementia

Michael Smith Foundation for Health Research/Pacific Alzheimer Research Foundation Scholar Award

Frontotemporal dementia is a progressive neurodegenerative syndrome, and the second most common cause of young-onset dementia after Alzheimer’s disease. Members of our team recently reported that loss-of-function mutations in the gene for a protein called progranulin cause 25 percent of frontotemporal dementia cases. Of these mutations, 30-40 percent are “nonsense mutations” that act as stop signs to prematurely end a process required to produce normal progranulin. When progranulin production ends too early, it leads to a shortened protein that cannot carry out the normal brain functions, eventually leading to dementia in the sixth decade.

The goal of this project is to investigate small molecule combinations that can bypass the abnormal “stop sign” in the progranulin gene, increasing the normal production of this important protein. The small molecule combinations will be refined and optimized to find the most effective combination. This approach, also referred to as “suppression of nonsense mutations”, offers the possibility of developing a new drug for patients with frontotemporal dementia cause by a progranulin mutation. The team also plans to develop a mouse model of frontotemporal dementia to test the small molecule combinations in a living organism.

The long-term goal of the project is to bring new drugs for frontotemporal dementia into clinical trials. An effective therapy would alleviate the devastating impact of dementia in many patients and their families, in BC and beyond.

End of Award Update

Source: CLEAR Foundation

We studied frontotemporal dementia (FTD) with the aim of developing novel drugs for this devastating condition. A subset of FTD patients have a genetic mutation that leads to reduced levels of an important protein called progranulin. Our project aimed to develop a drug that could counteract this genetic mutation. We used brain cells cultured in a dish to test new drugs and found a known antibiotic to have properties that could increase progranulin in this model.

This work laid the foundation for ongoing research to develop drugs to increase progranulin in patients with certain forms of FTD.