Major contributions
Yokota's research focuses on precision health and personalized genetic medicine using single strands of artificial DNA/RNA-like molecules called antisense oligonucleotides for
neuromuscular diseases. Yokota demonstrated the therapeutic potential of antisense oligonucleotides for
exon skipping, which can be designed to frame-disrupting
exons and restore the
reading frame and function of a mutated
gene by modulating
pre-mRNA splicing, leading to the improvement of skeletal muscle function accompanied by
dystrophin restoration for the first time in a severe animal model of
Duchenne muscular dystrophy (DMD). Based on the study,
viltolarsen, a
phosphorodiamidate morpholino oligomer antisense oligonucleotide, was developed for the treatment of DMD in collaboration with a Japanese pharmaceutical company. Viltolarsen was later approved by the
Pharmaceuticals and Medical Devices Agency in Japan and by the
FDA in the
United States in March and August 2020, respectively, after clinical trials conducted in Japan,
Canada, and the United States. Yokota's team further developed a potential treatment for nearly half of DMD patients using multiple antisense oligonucleotides and demonstrated therapeutic effects in a dystrophic mouse model. Supported by the
Heart and Stroke Foundation of Canada, the research team developed a cocktail of peptide-conjugated morpholinos (PPMOs) and restored expression of dystrophin in the myocardium and Purkinje fibers in the heart muscle of dystrophic animal models. Supported by the
Canadian Institutes of Health Research and Muscular Dystrophy Canada, Yokota's team is also developing antisense oligonucleotide-mediated therapy for
facioscapulohumeral muscular dystrophy using
lipid nanoparticles in collaboration with
Pieter Cullis. In 2020, they identified antisense oligonucleotides called
gapmers that knock down the expression of a toxic gene called
DUX4 in cell and mouse models for the treatment of facioscapulohumeral muscular dystrophy. Yokota's research identified ASO targets for skipping multiple
dysferlin (DYSF) exons (26-27 and 28-29), which were shown to enhance membrane resealing function in patient cells—a therapeutic approach applicable to 5-8% of dysferlinopathy patients globally. In 2022, Yokota's team identified
gapmers that selectively knocked down most of the mutated
mRNA for the treatment of
fibrodysplasia ossificans progressiva. With support from
CIHR and
muscular dystrophy Canada, the team also identified novel peptide-conjugated morpholinos called DG9-PMOs that effectively improved mouse models of DMD and
spinal muscular atrophy. == Honors ==
Selected publications
• Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E. Efficacy of morpholino systemic exon-skipping in Duchenne dystrophy dogs. Ann. Neurol., 2009, 65:667-76. • Echigoya Y, Lim K, Trieu N, Bao B, Miskew B, Vila MC, Novak JS, Hara Y, Lee J, Touznik A, Mamchaoui K, Aoki Y, Takeda S, Nagaraju K, Mouly V, Maruyama R, Duddy W, Yokota T. Quantitative antisense screening and optimization for exon 51 skipping in Duchenne muscular dystrophy. Mol Ther. 2017, 25(11): 2561-2572. • Echigoya Y, Nakamura A, Aoki Y, Nagata T, Kuraoka M, Urasawa N, Panesar D, Iversen P, Kole R, Maruyama R, Partridge T, Takeda S, Yokota T. Effects of systemic multi-exon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. U S A., 2017, 114 (16), 4213-4218. • Lim K, Echigoya Y, Nagata T, Kuraoka M, Kobayashi M, Aoki Y, Partridge T, Maruyama R, Takeda S, Yokota T. Efficacy of multi-exon skipping treatment in Duchenne muscular dystrophy dog model neonates. Mol. Ther. 2019, 27(1): 76-86. • Echigoya Y, Lim K, Melo D, Bao B, Trieu N, Mizobe Y, Maruyama R, Mamchaoui K, Tanihata J, Aoki Y, Takeda S, Mouly V, Duddy W, Yokota T. Exons 45-55 skipping using mutation-tailored cocktails of antisense morpholinos in the DMD gene. Mol. Ther. 2019, 27(11): 2005-17. • Lim K, Maruyama R, Echigoya Y, Nguyen Q, Khawaja H, Chandra S, Jones T, Jones P, Chen Y, Yokota T. Inhibition of DUX4 expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy. Proc. Natl. Acad. Sci. U S A. 2020, 117 (28), 16509-16515. • Lim K, Bittel A, Maruyama R, Echigoya Y, Nguyen Q, Huang Y, Dzierlega, Zhang A, Chen Y, Yokota T. DUX4 transcript knockdown with antisense 2'-O-methoxyethyl gapmers for the treatment of facioscapulohumeral muscular dystrophy. Mol. Ther. 2021, 29(2): 848-58. • Chiba S, Lim K, Sheri N, Anwar S, Erkut E, Shah A, Aslesh T, Woo S, Sheikh O, Maruyama R, Takano H, Kunitake K, Duddy W, Okuno Y, Aoki Y, Yokota T. eSkip-Finder: a machine learning-based web application and database to identify the optimal sequences of antisense oligonucleotides for exon skipping. Nucleic Acids Res. 2021, 49(W1):W193-W198. • Lim K, Woo S, Melo D, Huang Y, Dzierlega K, Shah MNA, Aslesh, Roshmi RR, Echigoya Y, Maruyama R, Moulton HM, Yokota T. Development of DG9 peptide-conjugated single- and multi-exon skipping therapies for the treatment of Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. U S A. 2022, 119 (9) e2112546119. • Aslesh T, Erkut E, Ren J, Lim KRQ, Woo S, Hatlevig S, Moulton HM , Gosgnach S, Greer J , Maruyama R, Yokota T. DG9 peptide-conjugated morpholino rescues phenotype in SMA model mice by reaching the CNS through a single subcutaneous administration. JCI Insight. 2023, e160516. • Anwar S, Roshmi RR, Woo S, Haque US, Lee J, Duddy WJ, Bigot A, Maruyama R, Yokota T. Antisense oligonucleotide-mediated exon 27 skipping restores dysferlin function in dysferlinopathy patient-derived muscle cells. Mol Ther Nucleic Acids. 2025, 36(1):102443. ==References==