Dr. Haakon Nygaard
Project Title: Chemical suppression of nonsense mutations for the treatment of frontotemporal dementia
Co-funding Partner: Michael Smith Health Research BC
Grant Name: 2016 Michael Smith Health Research Scholar Award
Grant Duration: 2016-2021 (five years)
Research Lay Summary:
Frontotemporal dementia is a progressive neurodegenerative syndrome, and the second most common cause of young-onset dementia after Alzheimer’s disease. Members of Dr.Nygaard’s team recently reported that loss-of-function mutations in the gene of a protein called progranulin caused 25 percent of frontotemporal dementia cases. Of these mutations, 30-40% 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 caused by a progranulin mutation. This research also plans to develop a mouse model of frontotemporal dementia to test the small molecule combinations in a living organism
Final Report(s):
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.