Stabilization of ALS/FTD hexanucleotide repeats via modulation of repair to reverse disease progression

2014  -  Toronto, ON, CA


The Hospital for Sick Children

Project description

40 human diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), myotonic dystrophy and Huntington’s disease, are inherited in a manner that the symptoms become more evident through family generations. These diseases become worse as the individual ages. These diseases are caused by mutations in repeated DNAs. Hexanucleotide repeat expansions at C9orf72 are the predominant cause of ALS and FTD, whereby ongoing repeat expansions occurring in the brain have been shown to correlate with disease age-of-onset, severity and progression. If one considers a gene as though it were a sentence such as THE CAT ATE THE FAT FAT RAT, typical mutations would be spelling errors, like THE GAT ATE THE FAT FAT RAT. This mutation would be the same in all family members, all with the same symptoms. However, in repeat-associated diseases the mutation would be THE CAT ATE THE FAT FAT FAT FAT RAT, and their children would inherit a further mutation; THE CAT ATE THE FAT FAT FAT FAT FAT FAT FAT FAT RAT and have more severe disease than their parents. Importantly, these mutations continue through the life of the patient in affected tissues; progressively getting larger making symptoms worse as they age.

Our research focuses on understanding this mutation in ALS/FTD with the long-term goal of being able to therapeutically modulate this mutation to treat affected families. Being able to arrest or reverse this repeat mutation (reducing or preventing the expansion of the number of ‘FAT’ repeat units) presents a therapeutic pathway to reduce disease progression and severity. We identified a DNA structure and set of proteins that are required to drive the expansions of the disease-causing repeats. Blocking these DNAs or proteins should block the expansion of the repeats. Specifically, with regard to ALS/FTD associated with GGGGC expansions we will identify factors that can beneficially modulate this disease causing mutation which highlights novel avenues aimed at therapeutic treatment by arresting or reversing the expansion mutations (THE CAT ATE THE FAT FAT FAT FAT FAT RAT down to THE CAT ATE THE FAT FAT RAT).

Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging

In 2011, the most common mutation causing ALS/FTD was shown to be a hexanucleotide repeat expansion in the C9orf72 gene, while non-affected individuals have genetically stable short repeat tracts.  Much can be learned about ALS/FTD from the research on >40 repeat diseases (DM1, HD, FRAXA etc), studied since 1991. Many paths exist for C9orf72 expansions to cause disease (transcription loss, toxic-RNAs, or toxic-peptides), and many labs are targeting these. The relative disease contribution of each path is unclear. However, C9orf72 expansions are the root of disease. Treatment that reverses expansions to non-pathogenic lengths would address all pathogenic avenues. Once repeats are contracted, patients would not require further treatment. This is the goal of our research proposal and would accelerate the development of better treatments for ALS/FTD, which could potentially be also applied to other diseases caused by repeat expansions.

 Anticipated outcome

Our ultimate goal is to therapeutically modulate C9orf72 repeat instability for clinical benefit. The experience of nearly twenty years in repeat-associated diseases gives my lab an advantage in assessing the association of this form of mutation with ALS/FTD, which will ensure the success of the proposed project. The results will have important implications upon the mechanism of this disease-causing mutation, the source of variability in instability and its relation to disease progression. Results will provide better understanding of the mechanism of ALS/FTD caused by C9orf72 repeat expansions and advance the advancement of treatment for ALS/FTD.