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Rohini Roy Roshmi, Toshifumi Yokota Department of Medical Genetics, University of Alberta, Edmonton, Alberta, CanadaCorrespondence: Toshifumi YokotaDepartment of Medical Genetics, University of Alberta, Edmonton, Alberta, CanadaTel +1 7804921102Fax +1 7804921998Email toshifum@ualberta.caAbstract: Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive disorder characterized by progressive muscle loss and cardiorespiratory complications. Mutations in the DMD gene that eliminate the production of dystrophin protein are the underlying causes of DMD. Viltolarsen is a drug of phosphorodiamidate morpholino oligomer (PMO) chemistry, designed to skip exon 53 of the DMD gene. It aims to produce truncated but partially functional dystrophin in DMD patients and restore muscle function. Based on a preclinical study showing the ability of antisense PMOs targeting the DMD gene to improve muscle function in a large animal model, viltolarsen was developed by Nippon Shinyaku and the National Center of Neurology and Psychiatry in Japan. Following clinical trials conducted in Japan, Canada, and the United States showing significant improvements in muscle function, viltolarsen was approved for medical use in Japan in March 2020 and the United States in August 2020, respectively. Viltolarsen is a mutation-specific drug and will work for 8% of the persons with DMD who carry mutations amenable to exon 53 skipping. This review summarizes the pharmacological profile of viltolarsen, important clinical trials, and challenges, focusing on the contribution of Japanese patients and researchers in its development.Keywords: phosphorodiamidate morpholino oligomer, exon skipping, dystrophin, efficacy, timeline, safety

We describe a method for removing systematic biases of column-averaged dry air mole fractions of CO2 (XCO2) and CH4 (XCH4) derived from short-wavelength infrared (SWIR) spectra of the Greenhouse gases Observing SATellite (GOSAT). We conduct correlation analyses between the GOSAT biases and simultaneously retrieved auxiliary parameters. We use these correlations to bias correct the GOSAT data, removing these spurious correlations. Data from the Total Carbon Column Observing Network (TCCON) were used as reference values for this regression analysis. To evaluate the effectiveness of this correction method, the tnzuncorrected/corrected GOSAT data were compared to independent XCO2 and XCH4 data derived from aircraft measurements taken for the Comprehensive Observation Network for TRace gases by AIrLiner (CONTRAIL) project, the National Oceanic and Atmospheric Administration (NOAA), the US Department of Energy (DOE), the National Institute for Environmental Studies (NIES), the Japan Meteorological Agency (JMA), the HIAPER Pole-to-Pole observations (HIPPO) program, and the GOSAT validation aircraft observation campaign over Japan. These comparisons demonstrate that the empirically derived bias correction improves the agreement between GOSAT XCO2/XCH4 and the aircraft data. Finally, we present spatial distributions and temporal variations of the derived GOSAT biases.

Hiroyuki Yokoyama,1 Takashi Hirai,1 Tetsuya Nagata,2 Mitsuhiro Enomoto,1 Hidetoshi Kaburagi,1 Li Leiyo,1 Takayuki Motoyoshi,1 Toshitaka Yoshii,1 Atsushi Okawa,1 Takanori Yokota2 1Department of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; 2Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo 113-8519, JapanCorrespondence: Takashi Hirai; Takanori Yokota Email Hirai.orth@tmd.ac.jp; tak-yokota.nuro@tmd.ac.jpPurpose: Pathological stimuli or injury to the peripheral nervous system can trigger neuropathic pain with common clinical features such as allodynia and hypersensitivity. Although various studies have identified molecules or genes related to neuropathic pain, the essential components are still unclear. Therefore, in this study, we investigated the molecular and genetic factors related to neuropathic pain.Methods: We extracted candidate genes in the dorsal root ganglion (DRG) from three nerve injury mouse models and a sham-operated model (sciatic nerve ligation and resection, sural nerve resection, spared nerve injury [SNI], and sham) using DNA microarray to elucidate the genes responsible for the neuropathic pain mechanism in the SNI model, which exhibits hypersensitivity in the hindpaw of the preserved sural nerve area. We eliminated as many biases as possible. We then focused on an upregulated endogenous vasopressin receptor and clarified whether it is closely associated with traumatic neuropathic pain using a knockout mouse and drug-mediated suppression of the gene.Results: Algorithm analysis of DNA microarray results identified 50 genes significantly upregulated in the DRG of the SNI model. Two independent genes—cyclin-dependent kinase-1 (CDK-1) and arginine vasopressin receptor 1A (V1a)—were subsequently identified as candidate SNI-specific genes in the DRG by quantitative PCR analysis. Administration of V1a agonist to wild-type SNI mice significantly alleviated neuropathic pain. However, V1a knockout mice did not exhibit higher hypersensitivity to mechanical stimulation than wild-type mice. In addition, V1a knockout mice showed similar pain behaviors after SNI to wild-type mice.Conclusion: Through the DNA microarray analysis of several neuropathic models, we detected specific genes related to chronic pain. In particular, our results suggest that V1a in the DRG may partially contribute to the mechanism of neuropathic pain.Keywords: neuropathic pain, arginine vasopressin 1a, peripheral nerve injury, dorsal root ganglion, microarray, molecular target

Quynh Nguyen,*,1 Kenji Rowel Q Lim,*,1 Toshifumi Yokota,1,21Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 2The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair, Edmonton, AB, Canada*These authors contributed equally to this workAbstract: Congenital muscular dystrophy (CMD) is a class of severe early-onset muscular dystrophies affecting skeletal/cardiac muscles as well as the central nervous system (CNS). Laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2 MD), also known as merosin-deficient congenital muscular dystrophy type 1A (MDC1A), is an autosomal recessive CMD characterized by severe muscle weakness and degeneration apparent at birth or in the first 6 months of life. LAMA2 MD is the most common congenital muscular dystrophy, affecting approximately 4 in 500,000 children. The most common cause of death in early-onset LAMA2 MD is respiratory tract infection, with 30% of them dying within the first decade of life. LAMA2 MD is caused by loss-of-function mutations in the LAMA2 gene encoding for the laminin-α2 chain, one of the subunits of laminin-211. Laminin-211 is an extracellular matrix protein that functions to stabilize the basement membrane and muscle fibers during contraction. Since laminin-α2 is expressed in many tissue types including skeletal muscle, cardiac muscle, Schwann cells, and trophoblasts, patients with LAMA2 MD experience a multi-systemic clinical presentation depending on the extent of laminin-α2 chain deficiency. Cardiac manifestations are typically associated with a complete absence of laminin-α2; however, recent case reports highlight cardiac involvement in partial laminin-α2 chain deficiency. Laminin-211 is also expressed in the brain, and many patients have abnormalities on brain imaging; however, mental retardation and/or seizures are rarely seen. Currently, there is no cure for LAMA2 MD, but various therapies are being investigated in an effort to lessen the severity of LAMA2 MD. For example, antisense oligonucleotide-mediated exon skipping and CRISPR-Cas9 genome editing have efficiently restored the laminin-α2 chain in mouse models in vivo. This review consolidates information on the clinical presentation, genetic basis, pathology, and current treatment approaches for LAMA2 MD.Keywords: LAMA2, exon skipping, genome editing, non-homologous end joining, phosphorodiamidate morpholino oligomer, CRISPR/Cas9

Yoji Saito,1 Takaaki Yokota,2 Masatsugu Arai,3 Yukio Tada,4 Masahiko Sumitani5 1Department of Anesthesiology, Shimane University Hospital, Shimane, Japan; 2Project Management Department, Shionogi & Co., Ltd, Osaka, Japan; 3Business Development Department, Shionogi & Co., Ltd, Osaka, Japan; 4Biostatistics Center, Shionogi & Co., Ltd, Osaka, Japan; 5Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Tokyo, Japan Introduction: Naldemedine is a peripherally-acting µ-opioid-receptor antagonist, approved in Japan for opioid-induced constipation (OIC). In two open-label, single-arm, Phase III studies, we evaluated the safety and efficacy of naldemedine in Japanese patients with OIC receiving regular-use opioids (COMPOSE-6) or prolonged-release oxycodone (COMPOSE-7) for chronic noncancer pain. Methods: Eligible Japanese adults with OIC and chronic noncancer pain received once-daily oral naldemedine 0.2 mg for 48 weeks, irrespective of food intake. Primary end points included measures of treatment-emergent adverse events (TEAEs), pain intensity, and opioid withdrawal. Secondary efficacy end points were evaluated at treatment week 2. Patient Assessment of Constipation Symptoms (PAC-SYM) and Quality of Life (PAC-QOL) scores were evaluated in both 48-week studies. Results: Of patients enrolled in COMPOSE-6 (N = 43) and COMPOSE-7 (N = 10), TEAEs were reported in 88% (95% CI 74.9–96.1) and 90% (95% CI 55.5–99.7), respectively. The most frequently reported TEAEs, nasopharyngitis and diarrhea, were mostly mild or moderate in severity. Assessments of pain intensity and opioid withdrawal remained stable over the 48-week treatment periods of both studies. The proportion of spontaneous bowel-movement responders at week 2 in COMPOSE-6 was 81.0% (95% CI 65.9–91.4) and 90.0% (95% CI 55.5–99.7) in COMPOSE-7. Significant and sustained improvements in PAC-SYM and PAC-QOL scores were also observed in both studies (all P

Kenji Rowel Q Lim,1 Rika Maruyama,1 Toshifumi Yokota1,2 1Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 2The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair, Edmonton, AB, Canada Abstract: Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500–5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by loss-of-function mutations in the DMD gene coding for dystrophin, a cytoskeletal protein that stabilizes the plasma membrane of muscle fibers. In September 2016, the US Food and Drug Administration granted accelerated approval for eteplirsen (or Exondys 51), a drug that acts to promote dystrophin production by restoring the translational reading frame of DMD through specific skipping of exon 51 in defective gene variants. Eteplirsen is applicable for approximately 14% of patients with DMD mutations. This article extensively reviews and discusses the available information on eteplirsen to date, focusing on pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials. Issues faced by eteplirsen, particularly those relating to its efficacy, will be identified. Finally, the place of eteplirsen and exon skipping as a general therapeutic strategy in Duchenne muscular dystrophy treatment will be discussed. Keywords: Duchenne muscular dystrophy, eteplirsen, Exondys 51, exon-skipping therapy, phosphorodiamidate morpholino oligomers

This paper deals with the Keller-Segel system with gradient dependent chemotactic sensitivity, ... where Ω ⊂ R n (n ∈ N) is a bounded domain with smooth boundary, and χ > 0, p ∈ (1,∞) are constants. The purpose of this paper is to establish stability of constant equilibria under some smallness conditions for the initial data. [ABSTRACT FROM AUTHOR]