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Drugs Jul 2020Viltolarsen (Viltepso in Japan) is a phosphorodiamidate morpholino antisense oligonucleotide being developed by Nippon Shinyaku, in collaboration with the National... (Review)
Review
Viltolarsen (Viltepso in Japan) is a phosphorodiamidate morpholino antisense oligonucleotide being developed by Nippon Shinyaku, in collaboration with the National Center of Neurology and Psychiatry (NCNP), for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen binds to exon 53 of the dystrophin mRNA precursor and restores the amino acid open-reading frame by skipping exon 53, resulting in the production of a shortened dystrophin protein that contains essential functional portions. In March 2020, intravenous viltolarsen received its first global approval in Japan for the treatment of DMD in patients with confirmed deletion of the dystrophin gene that is amenable to exon 53 skipping. Viltolarsen is under regulatory review in the USA and clinical trials continue in the USA, Canada and globally. This article summarizes the milestones in the development of viltolarsen leading to the first approval for DMD.
Topics: Drug Approval; Humans; Molecular Conformation; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense
PubMed: 32519222
DOI: 10.1007/s40265-020-01339-3 -
Translational Research : the Journal of... Sep 2020Extensive antibiotic use combined with poor historical drug stewardship practices have created a medical crisis in which once treatable bacterial infections are now... (Review)
Review
Extensive antibiotic use combined with poor historical drug stewardship practices have created a medical crisis in which once treatable bacterial infections are now increasingly unmanageable. To combat this, new antibiotics will need to be developed and safeguarded. An emerging class of antibiotics based upon nuclease-stable antisense technologies has proven valuable in preclinical testing against a variety of bacterial pathogens. This review describes the current state of development of antisense-based antibiotics, the mechanisms thus far employed by these compounds, and possible future avenues of research.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Gene Transfer Techniques; Humans; RNA, Antisense
PubMed: 32522669
DOI: 10.1016/j.trsl.2020.06.001 -
Frontiers in Cell and Developmental... 2021Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete.... (Review)
Review
Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of zebrafish and mammalian hearts, fast easily tractable development, and readily available genetic methods. Embryonic cardiac development is rapid and cardiac function is easy to observe and quantify. Reverse genetics, by using morpholinos and CRISPR-Cas9 to modulate gene function, make zebrafish a primary animal model for studies of candidate genes. Zebrafish are able to effectively regenerate their hearts following injury. However, less attention has been given to using zebrafish models to increase understanding of heart failure and cardiac remodeling, including cardiac hypertrophy and hyperplasia. Here we discuss using zebrafish to study heart failure and cardiac remodeling, and review zebrafish genetic, drug-induced and other heart failure models, discussing the advantages and weaknesses of using zebrafish to model human heart disease. Using zebrafish models will lead to insights on the pathomechanisms of heart failure, with the aim to ultimately provide novel therapies for the prevention and treatment of heart failure.
PubMed: 34095129
DOI: 10.3389/fcell.2021.662583 -
Movement Disorders : Official Journal... Aug 2019Currently, few disease-modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing... (Review)
Review
Currently, few disease-modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing ∼20 base pairs, that can potentially target any messenger RNA of interest. Antisense oligonucleotides often contain modifications to the phosphate backbone, the sugar moiety, and the nucleotide base. The development of antisense oligonucleotide therapies spinal muscular atrophy and Duchenne muscular dystrophy suggest potentially wide-ranging therapeutic applications for antisense oligonucleotides in neurology. Successes with these two diseases have heightened interest in academia and the pharmaceutical industry to develop antisense oligonucleotides for several movement disorders, including, spinocerebellar ataxias, Huntington's disease, and Parkinson's disease. Compared to small molecules, antisense oligonucleotide-based therapies have an advantage because the target disease gene sequence is the immediate path to identifying the therapeutically effective complementary antisense oligonucleotide. In this review we describe the different types of antisense oligonucleotide chemistries and their potential use for the treatment of human movement disorders. © 2019 International Parkinson and Movement Disorder Society.
Topics: Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Humans; Huntington Disease; Machado-Joseph Disease; Morpholinos; Movement Disorders; Oligonucleotides, Antisense; Parkinson Disease; Spinocerebellar Ataxias; tau Proteins
PubMed: 31283857
DOI: 10.1002/mds.27782 -
Journal of Neuromuscular Diseases 2021BackgroundEteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on...
BackgroundEteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production.ObjectiveTo report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort.MethodsAmbulatory patients aged 7-16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled.Results78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: -68.9 m; phase 2 studies: -67.3 m; external controls: -133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: -3.3%, phase 2 studies: -2.2%, external controls: -6.0%; p < 0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation.ConclusionsThis large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history.
Topics: Adolescent; Child; Disease Progression; Dystrophin; Exons; Humans; Male; Morpholinos; Muscular Dystrophy, Duchenne; Mutation; Vital Capacity
PubMed: 34120909
DOI: 10.3233/JND-210643 -
Cold Spring Harbor Protocols Apr 2022Microinjection is an important technique used to study development in the oocyte and early embryo. In , substances such as DNA, mRNA, and morpholino oligonucleotides...
Microinjection is an important technique used to study development in the oocyte and early embryo. In , substances such as DNA, mRNA, and morpholino oligonucleotides have traditionally been injected into , because of their large embryo size and the relatively long time from their fertilization to first division. In the past few decades, has become an important model in developmental biology; it is particularly useful in genetic studies. The advent and rapid development of CRISPR-Cas9 technology has provided an array of targeted gene manipulations for which is particularly suited. The equipment and protocol for microinjection is broadly transferable from There are important differences between the species to consider, however, including the smaller embryo size and faster embryo development time in There are a number of solutions and reagents that differ in concentration and composition as well. Here we describe a microinjection protocol specifically for studies in .
Topics: Animals; Microinjections; RNA, Messenger; Xenopus; Xenopus laevis
PubMed: 34244348
DOI: 10.1101/pdb.prot107644 -
Drugs Feb 2020Golodirsen (Vyondys 53), an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been developed... (Review)
Review
Golodirsen (Vyondys 53), an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been developed by Sarepta Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). In December 2019, intravenous golodirsen received its first global approval in the USA for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, based on positive results from a phase I/II clinical trial. Golodirsen is in phase III clinical development for the treatment of DMD worldwide. This article summarizes the milestones in the development of golodirsen leading to this first approval for DMD.
Topics: Drug Approval; Drug Development; Humans; Muscular Dystrophy, Duchenne; Oligonucleotides
PubMed: 32026421
DOI: 10.1007/s40265-020-01267-2 -
Molecules (Basel, Switzerland) Feb 2021Dengue fever is one of the most common viral infections affecting humans. It is an expanding public health problem, particularly in tropical and subtropical regions. No... (Review)
Review
Dengue fever is one of the most common viral infections affecting humans. It is an expanding public health problem, particularly in tropical and subtropical regions. No effective vaccine or antiviral therapies against Dengue virus (DENV) infection are available. Therefore, there is a strong need to develop safe and effective therapeutic strategies that can reduce the burden and duration of hospitalizations due to this life-threatening disease. Oligonucleotide-based strategies are considered as an attractive means of inhibiting viral replication since oligonucleotides can be designed to interact with any viral RNA, provided its sequence is known. The resultant targeted destruction of viral RNA interferes with viral replication without inducing any adverse effects on cellular processes. In this review, we elaborate the ribozymes, RNA interference, CRISPR, aptamer and morpholino strategies for the inhibition of DENV replication and discuss the challenges involved in utilizing such approaches.
Topics: Antiviral Agents; Dengue; Dengue Virus; Humans; Oligonucleotides; RNA Interference; Virus Replication
PubMed: 33670247
DOI: 10.3390/molecules26040956 -
Methods in Molecular Biology (Clifton,... 2022Techniques for disrupting gene expression are invaluable tools for the analysis of the biological role of a gene product. Because of its genetic tractability and... (Review)
Review
Techniques for disrupting gene expression are invaluable tools for the analysis of the biological role of a gene product. Because of its genetic tractability and multiple advantages over conventional mammalian models, the zebrafish (Danio rerio) is recognized as a powerful system for gaining new insight into diverse aspects of human health and disease. Among the multiple mammalian gene families for which the zebrafish has shown promise as an invaluable model for functional studies, the galectins have attracted great interest due to their participation in early development, regulation of immune homeostasis, and recognition of microbial pathogens. Galectins are β-galactosyl-binding lectins with a characteristic sequence motif in their carbohydrate recognition domains (CRDs), that constitute an evolutionary conserved family ubiquitous in eukaryotic taxa. Galectins are emerging as key players in the modulation of many important pathological processes, which include acute and chronic inflammatory diseases, autoimmunity and cancer, thus making them potential molecular targets for innovative drug discovery. Here, we provide a review of the current methods available for the manipulation of gene expression in the zebrafish, with a focus on gene knockdown [morpholino (MO)-derived antisense oligonucleotides] and knockout (CRISPR-Cas) technologies.
Topics: Animals; Galectins; Gene Knockdown Techniques; Mammals; Morpholinos; RNA; Zebrafish
PubMed: 35320539
DOI: 10.1007/978-1-0716-2055-7_23