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Modulating the ALS-associated C9orf72 repeat expansion in a murine model for therapeutic benefit

Principal Investigator:
  • Christopher Pearson, The Hospital for Sick Children
Team Members:
  • Ekaterina Rogaeva, University of Toronto

Project Overview

Mutations in a gene called C9ORF72 are the most common genetic cause of ALS. These mutations are unique in that unlike most other ALS-linked genes, where there is often a mistake in a single piece of DNA, C9ORF72 mutations involve a section of DNA that is abnormally repeated hundreds or even thousands of times. People with these repeat mutations make less of the normal C9ORF72 protein, but also produce more toxic substances in their motor neurons.

Dr. Christopher Pearson is an expert in studying repeat DNA expansions in disease and through his recent work, he has identified a previously unobserved characteristic about the C9ORF72 expansion mutation that makes it a potentially druggable target.

In this study, Dr. Pearson will determine if treating C9ORF72 model mice with a compound called fluorodeoxyuridine (FUdR) can cause these repeated DNA sections to shrink back to a less toxic size and restore production of the normal C9ORF72 protein. In collaboration with Dr. Ekaterina Rogaeva, an expert in studying a process called DNA called methylation, which can also alter C9ORF72 production, the team will examine how this process is affected by FUdR treatment.

The results gained from this project will help researchers to better understand the unique mutations in C9ORF72 and provide insight into novel therapeutic avenues to treat this form of the disease. If successful, the researchers would embark on a larger study to confirm the potential for FUdR as a treatment for C9ORF72-linked ALS.