The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Stanley T. Crooke - One of the best experts on this subject based on the ideXlab platform.
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Antisense Technology an overview and prospectus
Nature Reviews Drug Discovery, 2021Co-Authors: Stanley T. Crooke, Rosanne M. Crooke, Brenda F. Baker, Xue-hai LiangAbstract:Antisense Technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded Antisense oligonucleotide (ASO) drugs representing four chemical classes, two mechanisms of action and four routes of administration have been approved for commercial use, including the first RNA-targeted drug to be a major commercial success, nusinersen. Although all the approved drugs are for use in patients with rare diseases, many of the ASOs in late- and middle-stage clinical development are intended to treat patients with very common diseases. ASOs in development are showing substantial improvements in potency and performance based on advances in medicinal chemistry, understanding of molecular mechanisms and targeted delivery. Moreover, the ASOs in development include additional mechanisms of action and routes of administration such as aerosol and oral formulations. Here, we describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications. We also consider strategic issues such as target selection and provide perspectives on the future of the field.
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Antisense Technology: A Review.
The Journal of biological chemistry, 2021Co-Authors: Stanley T. Crooke, Brenda F. Baker, Xue-hai Liang, Rosanne M. CrookeAbstract:Antisense Technology is beginning to deliver on the broad promise of the Technology. Ten RNA-targeted drugs including eight single-strand Antisense drugs (ASOs) and two double-strand ASOs (siRNAs) have now been approved for commercial use, and the ASOs in phase 2/3 trials are innovative, delivered by multiple routes of administration and focused on both rare and common diseases. In fact, two ASOs are used in cardiovascular outcome studies and several others in very large trials. Interest in the Technology continues to grow, and the field has been subject to a significant number of reviews. In this review, we focus on the molecular events that result in the effects observed and use recent clinical results involving several different ASOs to exemplify specific molecular mechanisms and specific issues. We conclude with the prospective on the Technology.
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progress in Antisense Technology
Annual Review of Medicine, 2004Co-Authors: Stanley T. CrookeAbstract:With the recent FDA approval of Vitravene™, the first drug based on Antisense Technology to be commercialized, the new Technology has achieved an important milestone. Although the basic questions have been addressed, there are still many unanswered questions.
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Antisense drug Technology principles strategies and applications
2001Co-Authors: Stanley T. CrookeAbstract:Basic Principles of Antisense Technology Stanley T. Crooke Medicinal Chemistry of Antisense Oligonucleotides P. Dan Cook Analytical Methods for Antisense Drugs Janet M. Leeds and Lendell L. Cummins A Role for Antisense Technology in the Discovery of Highly Specific and Versatile Signal Transduction Inhibitors Brett P. Monia, Erich Koller, and William A. Gaarde Methods of Selecting Sites in RNA for Antisense Targeting Susan M. Freier Properties of Phosphorothioate Oligonucleotides Pharmacokinetic Properties in Animals Richard S. Geary, Rosie Z. Yu, Janet M. Leeds, Michael V. Templin, Tanya A. Watanabe, Scott P. Henry, and Arthur A. Levin Suborgan Pharmacokinetics Rosanne M. Crooke and Mark J. Graham Pharmacokinetic Properties in Humans Rosie Z. Yu, Steven L. Schoenfeld, Richard S. Geary, Tanya A. Watanabe, and Arthur A. Levin Toxicity of Antisense Oligonucleotides Arthur A. Levin, Scott P. Henry, David Monteith, and Michael V. Templin Clinical Safety of Phosphorothioate Oligodeoxynucleotides F. Andrew Dorr, Josephine M. Glover, and T. Jesse Kwoh General Pharmacology of Phosphorothioate Oligodeoxynucleotides C. Frank Bennett Properties of Advanced Novel Clinical Classes of Oligonucleotides Pharmacology of 2'-0-(2-Methoxy)ethyl Modified Antisense Oligonucleotides Nicholas M. Dean, Madeline Butler, Brett P. Monia, and Muthiah Manoharan Locked Nucleic Acid Jesper Wengel Antisense Properties of Peptide Nucleic Acid (PNA) Uffe Koppelhus and Peter J. Nielsen Phosphorodiamidate Morpholino Oligomers Patrick Iversen Oligonucleotide Conjugates in Antisense Technology Muthiah Manoharan Immune Stimulation by Oligonucleotides Arthur M. Krieg Pre-mRNA Splicing as a Target for Antisense Oligonucleotides Ryszard Kole and Danielle Mercatante Application of Antisense Oligonucleotides to the Study of CNS Protein Function Siew Peng Ho Antisense Approach to Isoform-Specific Blockade of Acetylcholinesterase Hermona E. Soreq and Shlomo Seidman Serine/Threonine Protein Phosphates Richard E. Honkanen Pharmacological Activities of Antisense Drugs: Inflammatory Diseases James G. Karras, Kathleen J. Myers, and Brenda F. Baker Respirable Antisense Oligonucleotides (RASONs) Jonathan W. Nyce Combined Antisense Therapy and Chemotherapy in Animal Models Dan Mercola Antisense Oligodesoxynucleotide Strategies in Renal and Cardiovascular Disease Hermann Haller, Christian Maasch, Duska Dragun, Maren Wellner, and Friedrich C. Luft The Development of Antisense Oligonucleotides as Antivirals Lisa R. Grillone Clinical Activities in Patients with Solid Tumors or Lymphoma Jon T. Holmlund Nucleic Acid Therapeutics for the Treatment of Human Leukemia Alan M. Gewirtz ISIS 2302, an Antisense Inhibitor of Intercellular Adhesion Molecule 1 (ICAM-1) William R. Shanahan, Jr. New Routes and Novel Formulations for Delivery of Antisense Oligonucleotides Gregory E. Hardee, Susan P. Weinbach, and Lloyd G. Tillman DNA-Binding Molecules Roland W. Burli and Heinz E. Moser Targeted Genome Modification via Triple Helix Formation Margaret A. Macris and Peter M. Glazer Intracellular Ribozyme Applications John J. Rossi
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Potential roles of Antisense Technology in cancer chemotherapy.
Oncogene, 2000Co-Authors: Stanley T. CrookeAbstract:Antisense Technology may play a major role in cancer chemotherapy. It is clearly a tool of exceptional value in the functionalization of genes and their validation as potential targets for cancer chemotherapy. Additionally, there is now substantial evidence that Antisense drugs are safe, and a growing body of data showing activity in animal models of human disease including cancer, and suggesting efficacy in patients with cancer. In this article, I review the progress in the Technology, the anticancer Antisense drugs in development and potential roles that Antisense Technology might play.
Rosanne M. Crooke - One of the best experts on this subject based on the ideXlab platform.
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Antisense Technology an overview and prospectus
Nature Reviews Drug Discovery, 2021Co-Authors: Stanley T. Crooke, Rosanne M. Crooke, Brenda F. Baker, Xue-hai LiangAbstract:Antisense Technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded Antisense oligonucleotide (ASO) drugs representing four chemical classes, two mechanisms of action and four routes of administration have been approved for commercial use, including the first RNA-targeted drug to be a major commercial success, nusinersen. Although all the approved drugs are for use in patients with rare diseases, many of the ASOs in late- and middle-stage clinical development are intended to treat patients with very common diseases. ASOs in development are showing substantial improvements in potency and performance based on advances in medicinal chemistry, understanding of molecular mechanisms and targeted delivery. Moreover, the ASOs in development include additional mechanisms of action and routes of administration such as aerosol and oral formulations. Here, we describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications. We also consider strategic issues such as target selection and provide perspectives on the future of the field.
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Antisense Technology: A Review.
The Journal of biological chemistry, 2021Co-Authors: Stanley T. Crooke, Brenda F. Baker, Xue-hai Liang, Rosanne M. CrookeAbstract:Antisense Technology is beginning to deliver on the broad promise of the Technology. Ten RNA-targeted drugs including eight single-strand Antisense drugs (ASOs) and two double-strand ASOs (siRNAs) have now been approved for commercial use, and the ASOs in phase 2/3 trials are innovative, delivered by multiple routes of administration and focused on both rare and common diseases. In fact, two ASOs are used in cardiovascular outcome studies and several others in very large trials. Interest in the Technology continues to grow, and the field has been subject to a significant number of reviews. In this review, we focus on the molecular events that result in the effects observed and use recent clinical results involving several different ASOs to exemplify specific molecular mechanisms and specific issues. We conclude with the prospective on the Technology.
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Antisense Technology: an emerging platform for cardiovascular disease therapeutics.
Journal of cardiovascular translational research, 2013Co-Authors: Richard G. Lee, Mark J. Graham, Brenda F. Baker, Jeff Crosby, Rosanne M. CrookeAbstract:Antisense oligonucleotides and small interfering RNAs, which suppress the translation of specific mRNA target proteins, are emerging as important therapeutic modalities for the treatment of cardiovascular disease. Over the last 25 years, the advances in all aspects of Antisense Technology, as well as a detailed understanding of the mechanism of action of Antisense drugs, have enabled their use as therapeutic agents. These advancements culminated in the FDA approval of the first chronically administered cardiovascular Antisense therapeutic, mipomersen, which targets hepatic apolipoprotein B mRNA. This review provides a brief history of Antisense Technology, highlights the progression of mipomersen from preclinical studies to multiple Phase III registration trials, and gives an update on the status of other cardiovascular Antisense therapeutics currently in the clinic.
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modulation of lipoprotein metabolism by Antisense Technology preclinical drug discovery methodology
Methods of Molecular Biology, 2013Co-Authors: Rosanne M. Crooke, Mark J. GrahamAbstract:Antisense oligonucleotides (ASOs) are a new class of specific therapeutic agents that alter the intermediary metabolism of mRNA, resulting in the suppression of disease-associated gene products. ASOs exert their pharmacological effects after hybridizing, via Watson-Crick base pairing, to a specific target RNA. If appropriately designed, this event results in the recruitment of RNase H, the degradation of targeted mRNA or pre-mRNA, and subsequent inhibition of the synthesis of a specific protein. A key advantage of the Technology is the ability to selectively inhibit targets that cannot be modulated by traditional therapeutics such as structural proteins, transcription factors, and, of topical interest, lipoproteins. In this chapter, we will first provide an overview of Antisense Technology, then more specifically describe the status of lipoprotein-related genes that have been studied using the Antisense platform, and finally, outline the general methodology required to design and evaluate the in vitro and in vivo efficacy of those drugs.
Emanuele Buratti - One of the best experts on this subject based on the ideXlab platform.
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assessment of the functional impact on the pre mrna splicing process of 28 nucleotide variants associated with pompe disease in gaa exon 2 and their recovery using Antisense Technology
Human Mutation, 2019Co-Authors: Elisa Goina, Andrea Dardis, Lorena Musco, Emanuele BurattiAbstract:Glycogen storage disease II (GSDII), also called Pompe disease, is an autosomal recessive inherited disease caused by a defect in glycogen metabolism due to the deficiency of the enzyme acid alpha-glucosidase (GAA) responsible for its degradation. So far, more than 500 sequence variants of the GAA gene have been reported but their possible involvement on the pre-messenger RNA splicing mechanism has not been extensively studied. In this work, we have investigated, by an in vitro functional assay, all putative splicing variants within GAA exon 2 and flanking introns. Our results show that many variants falling in the canonical splice site or the exon can induce GAA exon 2 skipping. In these cases, therefore, therapeutic strategies aimed at restoring protein folding of partially active mutated GAA proteins might not be sufficient. Regarding this issue, we have tested the effect of Antisense oligonucleotides (AMOs) that were previously shown capable of rescuing splicing misregulation caused by the common c.-32-13T>G variant associated with the childhood/adult phenotype of GSDII. Interestingly, our results show that these AMOs are also quite effective in rescuing the splicing impairment of several exonic splicing variants, thus widening the potential use of these effectors for GSDII treatment.
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glycogen reduction in myotubes of late onset pompe disease patients using Antisense Technology
Molecular Therapy, 2017Co-Authors: Elisa Goina, Paolo Peruzzo, Bruno Bembi, Andrea Dardis, Emanuele BurattiAbstract:Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed Antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c.-32-13T > G mutation. Using a minigene approach and patient fibroblasts, we successfully increased inclusion of exon 2 in the mRNA and GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, the use of these AMOs in patient myotubes results in a decreased accumulation of glycogen. To our knowledge, this is the only therapeutic approach resulting in a decrease of glycogen accumulation in patient tissues beside enzyme replacement therapy (ERT) and TFEB overexpression. As a result, it may represent a highly novel and promising therapeutic line for GSDII.
Thomas Herdegen - One of the best experts on this subject based on the ideXlab platform.
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Antisense Technology in the central nervous system by ronald a leslie a jackie hunter and harold a robertson
Trends in Neurosciences, 2000Co-Authors: Thomas HerdegenAbstract:Oxford University Press, 1999. £29.95 (xvii + 250 pages)ISBN 0 19 850316 4/8Antisense oligonucleotides (ASOs) can be considered a promising tool with which to analyse the functional knockout of a given protein in intact (that is, genetically unaltered) animals. There are very few other methods that have such a systematic approach: the application of antibodies or catalytic inhibition by antagonists are two such methods, but these can only antagonize the final product. The application of ASOs, however, interferes at an early stage with the generation of proteins by inhibition of transcription or translation. This approach is rivalled only by the construction of genetically fixed knockouts, although, again, these are handicapped by potential disadvantages such as mutation of other genes, nonphysiological ontogenetic development of the animal or compensatory upregulation of functionally similar proteins.Antisense Technology is particularly well suited to use in the CNS, a compartment that does not allow surgical intervention. The seclusion of the CNS, which includes the firewall of the blood–brain barrier, makes the local use of ASO particularly attractive. However, in order to achieve successful and controlled interference with the RNA machinery, serious problems must be considered and resolved, such as mode of application, control of action and effectiveness, specificity of protein suppression and the reproducibility of ASO efficacy.Antisense Technology in the Central Nervous System marks the endpoint of the first decade of ASO application in the brain. The final success of this development can be exemplified by the foundation of commercial organizations that sell and design ASOs by neurobiological pioneers of ASO research in the brain.The contributions made by the majority of the scientific leaders in the field are impressive. Very recently, state-of-the-art research in ASO Technology was reviewed1xElucidating cell signaling mechanisms using Antisense Technology. Koller, E. et al. Trends Pharmacol. Sci. 2000; 21: 142–148Abstract | Full Text | Full Text PDF | PubMed | Scopus (60)See all References1, and it seems that all aspects covered in the review are extensively discussed in this book. Antisense Technology in the Central Nervous System comprises both the rather detailed description of methods and the functional outcome of ASO application. The sequence of the chapters is logical. The first chapters focus critically on the optimization of the molecular design of ASOs, application of ASOs and the control of their specificity. However, it would have been more helpful if all the chapters and sections on methodological issues had been concentrated in this part. The second part of the book reports on the successful application of ASOs to prevent the expression specific proteins; for example, Fos transcription factor, dopamine D1, D2 and D3 receptors; opioid DOR and MOR receptors; and the neurotrophin trkB receptor. In the last part, the book includes further aspects of ASO with chapters on natural Antisense RNAs, the use of ASO for aptamer research or on ribozymes as regulators of gene expression in the CNS.The book is well illustrated throughout. There are clear diagrams that explain the concepts discussed and numerous tables containing protocols and conceptual approaches. The only serious criticism is the omission of a chapter on the use of decoy oligonucleotides, which can be used to silence DNA-binding proteins. Despite this small oversight, I would recommend this book as a useful reference source to all scientists who hope to elucidate the functions of specific proteins using Antisense Technology.
Leonidas A Phylactou - One of the best experts on this subject based on the ideXlab platform.
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assessing adenoviral hammerhead ribozyme and small hairpin rna cassettes in neurons inhibition of endogenous caspase 3 activity and protection from apoptotic cell death
Journal of Neuroscience Research, 2005Co-Authors: Ioannis Bantounas, Leonidas A Phylactou, Colin P J Glover, Stephen Kelly, Sachiko Iseki, James B UneyAbstract:Antisense Technology, including ribozyme and small interfering RNA, is being developed to mediate the down-regulation of specific intracellular genes. It was observed in this study that both antiluciferase ribozymes and short hairpin RNAs (shRNAs) could significantly reduce the activity of exogenously expressed luciferase in primary hippocampal neurons in a viral titer-dependent manner. shRNAs were more effective gene-silencing agents than ribozymes, although they exhibited some nonspecific gene-silencing effects at high viral titers. We also attempted to increase ribozyme efficacy by using a woodchuck hepatitis posttranscriptional regulatory element (WPRE) in the ribozyme expression cassette. The results showed that adenoviral vectors encoding specific ribozymes could silence the cellular expression of luciferase and endogenous procaspase-3 significantly. Furthermore, the antiprocaspase-3 ribozyme was shown to inhibit staurosporine-mediated cell death. The addition of a WPRE did not, however, increase or decrease ribozyme activity. As far as we are aware, this is the first example of adenovirally mediated delivery of hammerhead ribozymes being used to manipulate gene expression in primary neurons. The results therefore suggest that hammerhead ribozymes may be useful tools for studying neuronal gene function and have potential as therapeutic agents to treat CNS diseases. © 2005 Wiley-Liss, Inc.
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ribozyme and peptide nucleic acid based gene therapy
Advanced Drug Delivery Reviews, 2000Co-Authors: Leonidas A PhylactouAbstract:The recent discovery that RNA can act as a catalyst, apart from carrying genetic information, has given a new dimension to the field of gene therapy and has come to act synergistically with Antisense Technology. Ribozymes can be used to down-regulate (by RNA cleavage) or repair (by RNA trans-splicing) unwanted gene expression involved in disease. Hammerhead ribozymes have been used extensively to down-regulate gene expression in many diseases such as viral infections and cancer. Group I intron ribozymes on the other hand, have only been tried to repair inherited mutations but hold great promise for the future. Peptide nucleic acids (PNAs) Technology is another new Technology, which is currently been tried to block gene or RNA function. Gene therapy protocols need significant improvements in order to be used routinely in patients and hopefully, these new players should prove valuable to identifying new therapies for several untreated diseases.