Antisense Oligonucleotide Induced Exon Skipping As A Treatment For Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$363,055.00
Summary
Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to ....Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to dystrophin gene replacement therapies, due to the nature of the target (muscle fibres) and the size and complexity of the gene. This project will investigate an alternative genetic approach in cells expressing dystrophin (this gene is transcribed and processed differently in a variety cell types), whereby antisense oligonucleotides are used to redirect the processing of dystrophin pre-mRNA in the region of the DMD mutation. Although the DMD mutation would still be present at the gene level, the disease-causing mutation would be removed during the processing of the dystrophin pre-mRNA. Once a nonsense mutation has been removed or the reading frame restored from a DMD transcript, the resultant engineered dystrophin mRNA could be translated into a functional Becker-like protein.Read moreRead less
The Role Of Dysferlin In Muscular Dystrophy And Skeletal Muscle Membrane Repair.
Funder
National Health and Medical Research Council
Funding Amount
$316,667.00
Summary
Patients who lack the protein dysferlin have muscular dystrophy. These patients are unable to repair their muscle membranes, which get damaged during normal activities. A defect in membrane repair is a new pathway implicated in the muscular dystrophies, and it is likely that other patients will also have defective muscle membrane repair. We will find out how dysferlin mediates its role in membrane repair, and identify other dysferlin-interacting proteins, as these may also underlie disease.
Defintion Of Dystrophin Functional Domains According To Exon Boundaries To Optimise Splice Switching Therapies For DMD
Funder
National Health and Medical Research Council
Funding Amount
$520,765.00
Summary
Duchenne muscular dystrophy is a relentlessly progressive muscle wasting disorder, with a predictable outcome and no effective treatment. Splice manipulation has the potential to reduce the severity of the disease, improve the quality of life for patients and reduce health care costs. The definition of dystrophin functional domains according to exon boundaries will allow the most effective treatment strategies for each mutation to be developed.
Regulatory Mechanisms And Roles Of Calpains In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$439,813.00
Summary
The objectives are to understand the regulation and roles of calpains, which are proteases that break proteins in the building and repair of skeletal muscle. We will determine targets that calpains cleave and whether their location changes following activation, as well as the cellular factors regulating their activity. In addition, we will obtain information about the specific type of calpain dysfunction that occurs in particular patients with limb girdle muscular dystrophy 2A.
Diagnosing Hereditary Myopathies And Dystrophies With RNA Sequencing: Translating Research Innovations Into Diagnostic Practice
Funder
National Health and Medical Research Council
Funding Amount
$279,725.00
Summary
Despite recent advances in genetic testing, more than 50% of patients with hereditary neuromuscular disorders remain undiagnosed. This project aims to apply an alternative and the newest form of Next Generation Sequencing (NGS) testing strategy known as transciptome or RNA sequencing to clinical practice to further investigate patients who have remained undiagnosed despite WES and WGS.