Muscular dystrophy and neuromuscular diseases (NMDs) are devastating and poorly understood group of genetic disorders. Most of them are incurable. My overarching research goal is to discover, optimize, and translate novel therapies for these disorders.
Our research currently focuses on following projects:
1. Antisense and Exon Skipping Therapy
Antisense-mediated therapy is an exciting new approach to treat NMDs using DNA-like molecules. Our exon skipping therapy employs a cocktail of synthetic DNA-like molecules as a “DNA Band-Aid” to jump over (splice out) the mutated parts of the gene that block the effective creation of the protein. Our focus is on several NMDs including: Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), spinal muscular atrophy (SMA), and dysferlin-deficient muscular dystrophy. My research team has demonstrated the first systemic treatment using antisense therapy in mouse and dog models of Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder worldwide, and has led to Phase III clinical trials. Emerging evidence from fundamental studies through to Phase III clinical trials suggests that antisense therapy will be a robust, safe and effective therapy for many NMDs. Specifically, we 1) design effective antisense-mediated therapies by in silico analysis 2) develop and characterize novel in vivo disease models that appropriately recapitulate human NMDs, 3) measure the efficacy and safety of antisense therapies in cell and animal models.
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 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. Deciphering Molecular Mechanisms of Muscle Fatigue and Recovery
The cause of skeletal muscle fatigue has been investigated by researchers for more than 100 years, yet its molecular mechanisms remain poorly understood. Muscle fatigue is also a common complaint in muscular dystrophy patients, but it has not been well studied. Our recent studies indicate that dystrophin and dystrophin-associated proteins are involved in the recovery from muscle fatigue. Using transgenic and mutant mouse models, we focus on the role of dystrophin-associated proteins in the recovery from muscle fatigue.
The laboratory of Dr. Toshifumi Yokota invites applications for postdoctoral and graduate student positions in the Department of Medical Genetics at the University of Alberta. By utilizing integrative experimental and computational approaches, such as antisense oligonucleotides and CRISPR/Cas9, the focuses of our group are to develop novel molecular therapy for neuromuscular diseases and rare genetic diseases. Our group is actively collaborating with the world-class researchers and industry partners. The highly interdisciplinary and collaborative environment of our group provides unique career development opportunities for the postdoc trainees and graduate students. The program is run by Dr. Toshifumi Yokota, Assistant Professor and the Muscular Dystrophy Canada Research Chair. His laboratory is renowned internationally for its work on the development of exon skipping/antisense technology as well as the study on animal models. The CIHR Program will focus on advancing novel therapies for genetic diseases.
Note: the representative publications of the PI for independent and collaborative research includes
- Echigoya Y et al (2017) Proc. Natl. Acad. Sci. U S A., 114:4213-8.
- Nakamura A et al (2017) J. Hum. Genet., 62(4):459-463.
- Kamaludin AA et al (2016) Hum. Mol. Genet., 25(17):3798-3809.
- Nakamura A et al (2016) J. Hum. Genet., 61(7):663-7.
- Rodrigues M et al (2016) Sci. Rep., 6, 38371
- Echigoya Y et al (2015) Mol. Ther. Nucleic Acids., 4 (2), e225
- Pandey SN et al (2014) Mol. Ther., 22(2):390-6.
- Aoki Y et al (2013) Hum. Mol. Genet., 22(24):4914-28.
- Aoki Y et al (2012) Proc. Natl. Acad. Sci. U S A., 109:13763-8.
- Taniguchi M et al (2011) Nature, 478:127–131.
Located in Edmonton, Alberta, Canada, the Faculty has been internationally recognized as among the world’s top 50 medical schools and as one of Canada’s premier health-education institutions. The University is currently home to 39,000 students and 15,000 faculty and staff.
Postdoctoral Fellows: Applicants should have a Ph.D. degree (or equivalent) in biomedical sciences. Strong background in one or more of the following areas i) RNA biochemistry, ii) neurology, iii) molecular biology, iv) muscle biology, and v) mammalian cell biology. Mouse model experience is not required, but highly desirable. In order to qualify as a postdoc, the individual must be within 5 years of receiving their PhD.
Successful candidates will be offered competitive salary commensurate with experience and accomplishments.
All applicants should have good spoken and written communication skills in English. Interested applicants should send i) a cover letter briefly describing your previous experience and your future research interest/plan, ii) a curriculum vitae, and iii) contact information of at least three references to Dr. Toshifumi Yokota (firstname.lastname@example.org). Review of applications will continue until the position is filled.
Sources of Funding:
Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), National Institutes of Health (USA), Canada Foundation for Innovation, Alberta Enterprise and Advanced Education, Women and Children's Health Research Institute, Parent Project Muscular Dystrophy (USA), Jesse's Journey- The Foundation for Gene and Cell Therapy, Gilbert K. Winter Fund, Alberta Innovates: Health Solutions, University Hospital Foundation, International FOP Association, Rare Disease Foundation, FSH Society, Heart & Stroke Foundation of Alberta, BC Children’s Hospital Foundation.
We gratefully acknowledge the funding from The Friends of Garrett Cumming Research Fund, HM Toupin Neurological Science Research Fund, Muscular Dystrophy Canada, and Slipchuk SMA Research Fund.
47. Touznik A, Maruyama R, Hosoki K, Echigoya Y, Yokota T (2017) LNA/DNA mixmer-based antisense oligonucleotides correct alternative splicing of the SMN2 gene and restore SMN protein expression in type 1 SMA fibroblasts. Sci Rep. 7(1):3672.
46. Echigoya Y, Nakamura A, Nagata T, Urasawa N, Lim KRQ, Trieu N, Panesar D, Kuraoka M, Moulton HM, Saito T, Aoki Y, Iversen P, Sazani P, Kole R, Maruyama R, Partridge T, Takeda S, Yokota T (2017) Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. U S A.,114:4213-8.
45. Nakamura A, Shiba N, Miyazaki D, Nishizawa H, Inaba Y, Fueki N, Maruyama R, Echigoya Y, Yokota T (2017) Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy. J. Hum Genet. 62(4):459-463
44. Maruyama R, Echiogya Y, Caluseriu O, Aoki Y, Takeda S, Yokota T (2017) Systemic Delivery of Morpholinos to Skip Multiple Exons in a Dog Model of Duchenne Muscular Dystrophy. Methods Mol Biol. 1565:201-213
43. Lim KRQ, Maruyama R, Yokota T (2017) Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017; 11: 533-545.
42. Kamaludin AA, Smolarchuk C, Bischof JM, Eggert R, Greer JJ, Ren J, Lee JJ, Yokota T, Berry FB, Wevrick R. (2016) Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes. Hum Mol Genet. 25(17):3798-3809.
41. Rodrigues M, Echigoya Y, Maruyama R, Lim KRQ, Fukada SI, Yokota T (2016) Impaired regenerative capacity and lower revertant fibre expansion in dystrophin-deficient mdx muscles on DBA/2 background. Sci Rep. 2016; 6: 38371.
40. Bao B, Maruyama R, Yokota T.(2016) Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy. Intractable Rare Dis Res. 5(3):168-176.
39. Nakamura A, Fueki N, Shiba N, Motoki H, Miyazaki D, Nishizawa H, Echigoya Y, Yokota T, Aoki Y, Takeda S (2016) Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy. J Hum Genet. 61(7):663-7.
38. Miskew Nichols B, Aoki Y, Kuraoka M, Lee JJA, Takeda S, Yokota T (2016) Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy. J Vis Exp. 111: e53776
37. Rodrigues M, Echigoya Y, Fukada S, Yokota T (2016) Current Translational Research and Murine Models For Duchenne Muscular Dystrophy. J Neuromuscul Dis. 3(1): 29-48.
36. Lee JJA, Yokota T (2016) Translational research in nucleic acid therapies for muscular dystrophies. In Translational Research in Muscular Dystrophy (pp. 87-102), DOI: 10.1007/978-4-431-55678-7 © Springer., Tokyo, Japan
35. Bao B, Yokota T. (2015) Potential of anitisense therapy for facioscapulohumeral muscular dystrophy. Expert Opin Orphan Drugs. 3(12):1365-1374.
34. Guncay A, Yokota T. (2015) Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold? Future Med Chem. 7(13):1631-5.
33. Pandey SN, Kesari A, Yokota T, Pandey GS (2015) Muscular Dystrophy: Disease Mechanisms and Therapies. Biomed. Res. Int., 2015:456348
32. Yu X, Bao B, Echigoya Y, Yokota T (2015) Dystrophin-deficient large animal models: translational research and exon skipping. Am J Transl Res. 7(8):1214-31.
31. Nichols B, Takeda S, Yokota T (2015) Nonmechanical roles of dystrophin and associated proteins in exercise, neuromuscular junctions, and brains. Brain Sci. 5: 275-298.
30. Echigoya Y, Mouly V, Garcia L, Yokota T (corresponding), Duddy W (2015) In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in Duchenne muscular dystrophy. PLoS ONE 10(3): e0120058
29. Echigoya Y, Aoki Y, Miskew B, Panesar D, Touznik A, Nagata T, Tanihata J, Nakamura A, Nagaraju K, Yokota T (2015) Long-term efficacy of systemic multi-exon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice. Mol. Ther. Nucleic Acids. 4: e225.
28. Touznik A, Lee J, Yokota T (2014) New developments in exon skipping and splice modulation therapy for neuromuscular diseases. Expert Opin. Biol. Ther. 14(6):809-19
27. Echigoya Y, Yokota T (2014) Skipping multiple exons of dystrophin transcripts using cocktail
antisense oligonucleotides. Nucleic Acid Ther., 24(1):57-68.
26. Pandey SN, Lee YC, Yokota T, Chen YW (2014) Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice. Mol. Ther., 22(2):390-6.
25. Yokota T, Miyagoe-Suzuki Y, Ikemoto T, Takeda S (2014) Alpha1-Syntrophin deficient mice exhibit impaired muscle force recovery after osmotic shock. Muscle Nerve, 49(5):728-35
24. Lee J, Yokota T (2013) Antisense therapy in neurology. J. Pers. Med. 3, 144-176
23. Aoki Y, Nagata T, Yokota T, Nakamura A, Partridge T, Takeda S (2013) Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin α2 chain-null congenital muscular dystrophy mice. Hum. Mol. Genet., 22(24):4914-28.
22. Aoki Y, Yokota T, Wood M (2013) Development of multiexon-skipping
antisense oligonucleotide therapy for Duchenne muscular dystrophy. Biomed. Res. Int., 2013, 402369.
21. Echigoya Y*, Lee J*, Rodrigues M* (*equally contributed), NagataT, Tanihata J, Nozohourmehrabad A, Panesar D, Miskew B, Aoki Y, Yokota T (2013) Mutation Types and Aging Differently Affect Revertant Fiber
Expansion in Dystrophic Mdx and Mdx52 Mice. PLoS One. 8(7):e69194.
20. Aoki Y, Yokota T (corresponding), Nagata T, Nakamura A, Tanihata J, Saito T, Duguez SMR, Nagaraju K, Hoffman EP, Partridge T, Takeda S (2012) Bodywide skipping of exons 45-55 in dystrophic mdx52 mice by systemic antisense delivery. Proc. Natl. Acad. Sci. U S A., 109(34):13763-8.
19. Yokota T (corresponding), Nakamura A, Nagata T, Saito T, Kobayashi M, Aoki Y, Echigoya Y, Partridge T, Hoffman E, Takeda S (2012) Extensive and prolonged restoration of dystrophin expression with vivo-morpholino-mediated multiple exon skipping in dystrophic dogs. Nucleic Acid Ther., 22(5):306-15. *Featured Article
18. Yokota T (corresponding), Duddy W, Echigoya Y, Kolski H (2012) Exon skipping for nonsense mutations in Duchenne muscular dystrophy: Too many mutations, too few patients? Expert Opin. Biol. Ther., 12(9):1141-52.
17. Taniguchi M, Kobayashi M, Kanagawa M, Yu C, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T (2011) Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature, 478:127–131.* Faculty of 1000 recommended paper (Factor 6) selection.
16. Hoffman EP, Bronson A, Baudy AR, Yokota T, Takeda S, Connor EM (2011) Restoring dystrophin expression in Duchenne muscular dystrophy muscle: Progress in exon-skipping and stop codon read-through. Am. J. Pathol., 179(1):12-22.
15. Yokota T (corresponding), Hoffman E, Takeda S (2011) Antisense oligo-mediated multi-exon-skipping in a dog model of Duchenne muscular dystrophy. Methods Mol. Biol., Vol. 709, Pt. 3, 299-312, DOI: 10.1007/978-1-61737-982-6_20 © Humana Press Inc., Totowa, NJ
14. Lu QL, Yokota T, Takeda S, Garcia L, Muntoni F, Partridge T. (2011) The status of exon skipping as a therapeutic approach to Duchenne muscular dystrophy, Mol. Ther.,19:9-15.
13. Aoki Y , Nakamura A, Yokota T, Saito T, Okazawa H, Nagata T, Takeda S (2010) In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. Mol. Ther., 18:1995-2005.
12. Saito T, Nakamura A, Aoki Y, Yokota T, Okada T, Osawa M, Takeda S (2010) Antisense PMO found in dystrophic dog model was effective in cells from exon 7-deleted DMD patient. PLoS One, 2010; 5:e12239.
11. Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E (2009) Efficacy of morpholino systemic exon-skipping in Duchenne dystrophy dogs. Ann. Neurol., 65:667-76. * Faculty of 1000 exceptional paper (Factor 10) selection
10. Yokota T, Takeda S, Lu QL, Partridge T, Nakamura A, Hoffman E (2009) *\A renaissance for anti-sense oligonucleotide drugs in neurology: Exon-skipping breaks new ground. Arch. Neurol., 66:32-8. *Cover image selection
9. Sato K, Yokota T, Ichioka S, Shibata M, Takeda S (2008) Vasodilation of intramuscular arterioles under shear stress in dystrophin-deficient skeletal muscle is impaired through decreased nNOS expression. Acta Myol., 27:30-6.
8. Yokota T (corresponding), Duddy W, Partridge T (2007) Optimizing exon skipping therapies for DMD, Acta Myol., 26:179-84.
7. Yokota T (corresponding), Emidio P, Duddy W, Kanneboyina N (2007) Potential of exon skipping therapy for Duchenne muscular dystrophy, Expert Opin. Biol. Ther., 7:831-42.
6. Yokota T, Lu QL, Morgan JE, Davies KE, Fisher R, Takeda S, Partridge T (2006) Expansion of revertant fibers in dystrophic mdx muscles reflects activity of muscle precursor cells and serves as index of muscle regeneration. J. Cell Sci., 119: 2679-87.
5. Lu QL, Rabinowitz A, Chen YC, Yokota T, Yin H, Alter J, Jadoon A, Bou-Gharios G, Partridge T (2005) Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc. Natl. Acad. Sci. U S A., 102:198-203.
4. Munehira Y, Ohnishi T, Kawamoto S, Furuya A, Shitara K, Imamura M, Yokota T, Takeda S, Amachi T, Matsuo M, Kioka N, Ueda K (2004) Alpha1-syntrophin modulates turnover of ABCA1. J. Biol. Chem., 9; 279:15091-5.
3. Hosaka Y*, Yokota T* (*Equally Contributed), Miyagoe-Suzuki Y, Yuasa K, Imamura M, Matsuda R, Ikemoto T, Kameya S, Takeda S (2002) Alpha1-syntrophin-deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration, J. Cell Biol., 158: 1097-1107.
2. Sakamoto M, Yuasa K, Yoshimura M, Yokota T, Ikemoto T, Suzuki M, Dickson G, Miyagoe-Suzuki Y, Takeda S (2002) Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene, Biochem. Biophys. Res. Commun., 293:1265-1272.
1. Yokota T, Hosaka Y, Tsukita K, Kameya S, Shibuya S, Matsuda R, Wakayama Y, Takeda S (2000) Aquaporin-4 is absent at the sarcolemma and at perivascular astrocyte endfeet in alpha1-syntrophin knockout mice, Proc. Jpn. Acad. 76B:22-27.
Rika Maruyama, PhD
Aleksander Touznik, MSc
Graduate Student, BSc
Postdoctoral Fellow (2015 - 2017)
Postdoctoral Fellow (2012 - 2017)
Intern Graduate Student (2016)
Lab Technician (2015 - 2016)
Graduate Student (2014 - 2016)
Undergraduate Student (2016)
Graduate Student (2014 - 2016)
Undergraduate Student (2015 - 2016)
Undergraduate Student (2015)
Undergraduate Student (2013-2015)
Undergraduate Student (2014 - 2015)
Undergraduate Student (2012 - 2015)
Undergraduate Student (2014)
Undergraduate Student (2014 - 2016)
Undergraduate Student (2013)
Undergraduate Student (2012 - 2013)
Undergraduate Student (2012)
Any contribution toward our efforts to rescue muscular dystrophy and neuromuscular diseases would be highly valued and respected. Arrangements can be managed through the Dean's Office, Faculty of Medicine and Dentistry - Development. Please contact Dr. Toshifumi Yokota to learn about how your support would help.