The Rachel Fund

The Rachel Fund was founded in 2005 by Tribute Communities with the goal of advancing medical and scientific knowledge related to .

Thanks to the ongoing and generous financial support from Tribute Communities, Muscular Dystrophy Canada continues to fund research to better understand the genetic, cellular, and biochemical processes involved in myotonic dystrophy, and to develop therapies for its treatment.

Current Grants

The roles of MBNL proteins in the pathogenesis of myotonic dystrophy


Principle Investigator: Pascal Chartrand, PhD, University of Montreal

Co-funder: CIHR Institute of Musculoskeletal Health and Arthritis

Abstract: Myotonic dystrophy type 1 (DM1) is caused by an expansion of CUG-triplet repeats in the DMPK mRNA. The RNA-binding protein Muscleblind-like 1 (MBNL1) binds the UGCU motif in RNA and it is involved in the aggregation of mutant CUG-repeat RNA into nuclear foci. MBNL1 also has several normal functions in the cell; as an alternative splicing factor, and as a regulator of the cytoplasmic localization of mRNA. Non-disease mRNA bound by MBNL1 do not form nuclear foci, and it is not understood why MBNL1 causes the nuclear retention and aggregation of CUG-repeat mRNA. In this project, a team of three investigators will use live-cell microscopy, purification of RNA aggregates and biochemical approaches to elucidate the mechanism of MBNL1 and CUG-repeat RNA aggregate formation in DM1, and also define the role of MBNL1 in cytoplasmic mRNA localization. This work will provide important insights into the mechanisms of toxic RNA aggregate formation, the process through which they perturb the functions of MBNL factors, as well as the ensuing impact on the intracellular trafficking of key MBNL1 target mRNAs. Understanding these pathways will allow the development of new drugs to inhibit the nuclear retention of the mutant DMPK mRNA in DM1 patients or that help to restore the normal localization properties of mistargeted cellular mRNAs.

Modulating Disease-Associated Repeat Instability


Principle Investigator: Christopher Pearson, PhD, University of Toronto.

Co-funder: CIHR Institute of Musculoskeletal Health and Arthritis

Abstract: Modulating disease-associated repeat instability 40 human diseases, including myotonic dystrophy & Huntington’s disease are inherited in a manner that the symptoms become more evident through family generations. These diseases also become worse as the individual ages. These diseases are caused by mutations in repeated DNAs. 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 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 can also continue through the life of the patient in affected tissues; progressively getting larger making symptoms worse as they age. My research focuses on understanding this mutation with the long-term goal of being able to 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. The mutation of DNA repeats in these diseases occurs by mistakes during repair of damaged DNA. We identified a set of proteins that are required to drive the expansions of the disease-causing repeats. Blocking these proteins should block the expansion of the repeats. Specifically with regard to myotonic dystrophy we will identify drugs 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.

Evaluation of peptide antisense oligonucleotides as gene therapy for myotonic dystrophy


Principle Investigators: Jack Puymirat, CHU Quebec, and Dr. Matthew Wood, Oxford, UK

Co-funder: AFM (France)

Abstract: Myotonic dystrophy type 1 (DM1), an autosomal dominant multisystemic disorder, is the most common adult form of muscular dystrophy. A second form of DM, DM2, exists, which shares several manifestations of DM1. No treatment is presently available for DM1 and DM2. DM1 and DM2 are caused by CTG and CCTG repeat expansions in the 3’UTR for DM1 and in intron-1 for DM2 in their respective gene. The currently favoured pathogenic mechanism, spliceopathy, involves an RNA gain-of-function mechanism whereby repeat-containing transcripts from the expanded allele accumulate in affected cell nuclei and bind nuclear proteins involved in regulating alternative splicing. Among the different therapeutic approaches, two antisense oligonucleotide (AO) strategies have been developed during the last years. The first is the use of (CAG)n-steric blocking AOs (PMO-AOs), which prevent the sequestration of nuclear proteins to the CUG repeats. The second approach is to eliminate the toxic RNA from cell by using AOs-inducing RNA cleavage. The proof-of-principle has been demonstrated for both approaches in vitro, in human DM1 myoblasts, and in vivo, in mouse models of DM1, after intramuscular injection. In both cases, however, none of these two strategies have been confirmed by systemic administration because of poor delivery of AO into skeletal muscles. No data are currently available for DM2. Critical to the therapeutic success of AO-based treatment will be the ability to deliver AOs systemically to all affected tissues. The availability of AOs, which either block the binding of nuclear proteins to the repeats or induce RNA cleavage, will be a major tool not only to develop a gene therapy for DM but also to understand the pathogenesis of DM1 and DM2.

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