Discover, optimize, and translate novel therapies for neurological and musculoskeletal disorders
Dr. Toshifumi Yokota, Ph.D.
The Friends of Garrett Cumming & Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair
Our research currently focuses on following projects:
1. Antisense and Genome Editing Therapies
Antisense-mediated therapy is an exciting new approach to treating diseases using DNA-like molecules. These molecules, called antisense oligonucleotides, act like a stitch or Band-Aid to mitigate the effects of genetic mutations and restore the gene function. By utilizing integrative experimental and computational approaches, such as antisense oligonucleotides, CRISPR/Cas9 genome editing, and machine-learning, the focuses of our group are to develop novel personalized molecular therapies for neuromuscular and musculoskeletal diseases. Our focus is on several devastating genetic diseases, including Duchenne/Becker muscular dystrophy (DMD/BMD), dysferlin-deficient muscular dystrophy (limb-girdle muscular dystrophy type 2b, Miyoshi myopathy, and distal myopathy with anterior tibial onset), facioscapulohumeral muscular dystrophy (FSHD), spinal muscular atrophy (SMA), and fibrodysplasia ossificans progressiva (FOP).
2. Dystrophin Revertant Fibre Analysis
Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders, occurring once per 3,500 male births, caused by a lack of a protein called dystrophin. Interestingly, in many DMD patients and animal models, a small proportion of muscle fibres show strong dystrophin positive staining called "revertant fibres". We previously identified the mechanism by which revertant fibres arise from spontaneous exon skipping (alternative splicing) and proliferate through muscle regeneration with activation of muscle precursor (stem) cells. The aim of the current project is to elucidate the mechanisms underlying generation and proliferation of revertant fibres. By analyzing these fibres, researchers may be able to identify new and more effective targets for treatments of DMD.
3. Muscle Membrane Imaging
Some forms of muscular dystrophy patients including limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal myopathy with anterior tibial onset (DMAT) have a primary defect in skeletal muscle membrane repair. Their muscle fibres are unable to effectively repair the damaged muscle membrane. We analyze the molecular mechanisms involved in muscle membrane repair machinery with our state-of-the-art imaging infrastructure including multi-photon (two-photon) laser microscope. A better understanding of this process could lead to better treatments for patients. We are also developing antisense drugs to treat them.
4. Role of Water Channel Aquaporins in Muscle and Brain
A water channel Aquaporin-4 (AQP4) is known to selectively express in the fast-twitch skeletal muscle fibres and at the perivascular blood-brain-barrier (BBB) in the brain; however its physiological function remains poorly understood. In the past ten years, we have published several key findings related to the role of AQP4 in muscle fatigue and recovery using mutant mouse models. These include regulation of water flow across muscle membrane (sarcolemma) by AQP4 against osmotic changes and the recovery of muscle force generation after osmotic changes or exercise. The goal of our research program is to characterize the role of AQP4 in response to the muscle exercise and fatigue in muscles and brains.