Engineering Tumor-specific Oncolytic Adenoviruses with Small Molecule-controlled Expanded Tropisms PDF Download
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Author: Shigeki Joseph Miyake-Stoner
Publisher:
ISBN:
Category :
Languages : en
Pages : 133
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Book Description
A promising new strategy for cancer therapy is the use of engineered oncolytic viruses, adapted from their natural properties of seeking out and destroying cells to effectively find and specifically eliminate cancer cells. The overarching goal of the work presented here is to engineer powerful new adenoviruses that can preferentially infect tumor cells via disparate receptors, and replicate exclusively in cells that have lost tumor suppressor pathways. Since the creation of adenoviruses with novel tropism is limited by the ability to build and test new genetic designs, we desired targetable oncolytic adenoviruses with a modular platform that would enable rapid identification of new and controllable targeting moieties. We employed the property of rapamycin-induced FRB/FKBP heterodimerization to construct adenoviruses with chemically-controlled tropism by inserting FRB into the adenovirus and genetically encoding a functionalized FKBP fusion protein. We validated the targeting of this new class of viruses in culture using a panel of NCI breast cancer cell lines, targeting the frequently-upregulated cancer marker EGFR. We demonstrate that our targeting components are compatible with other virus modifications and that new adenoviruses with these mutations are able to infect and destroy a model of intractable triple negative breast cancer. Based on our findings, rapid discovery of effective targeting moieties for oncolytic adenoviruses should be possible, and we should avoid limiting the potency of future vectors by disrupting the highly evolved adenovirus capsid structure. While oncolytic adenoviruses have already shown to be safe in clinical trials, we have improved the replication specificity of an oncolytic virus based on the function of adenovirus genes that overlap with frequent tumor mutations. It has been shown that mutation in adenovirus E1A can prevent its inactivation of cell cycle-regulator retinoblastoma protein (Rb), and this mutation is the basis of selectivity for an oncolytic adenovirus in clinical trials. However, adenovirus also encodes E4orf6/7, which acts downstream of Rb by activating the cellular transcription factor E2F1 that also drives the cell cycle. We have combined mutations in E1A and E4orf6/7 and discovered highly selective oncolytic adenoviruses that have the promise to be the basis for safe and potent oncolytic cancer therapies.
Author: Shigeki Joseph Miyake-Stoner
Publisher:
ISBN:
Category :
Languages : en
Pages : 133
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Book Description
A promising new strategy for cancer therapy is the use of engineered oncolytic viruses, adapted from their natural properties of seeking out and destroying cells to effectively find and specifically eliminate cancer cells. The overarching goal of the work presented here is to engineer powerful new adenoviruses that can preferentially infect tumor cells via disparate receptors, and replicate exclusively in cells that have lost tumor suppressor pathways. Since the creation of adenoviruses with novel tropism is limited by the ability to build and test new genetic designs, we desired targetable oncolytic adenoviruses with a modular platform that would enable rapid identification of new and controllable targeting moieties. We employed the property of rapamycin-induced FRB/FKBP heterodimerization to construct adenoviruses with chemically-controlled tropism by inserting FRB into the adenovirus and genetically encoding a functionalized FKBP fusion protein. We validated the targeting of this new class of viruses in culture using a panel of NCI breast cancer cell lines, targeting the frequently-upregulated cancer marker EGFR. We demonstrate that our targeting components are compatible with other virus modifications and that new adenoviruses with these mutations are able to infect and destroy a model of intractable triple negative breast cancer. Based on our findings, rapid discovery of effective targeting moieties for oncolytic adenoviruses should be possible, and we should avoid limiting the potency of future vectors by disrupting the highly evolved adenovirus capsid structure. While oncolytic adenoviruses have already shown to be safe in clinical trials, we have improved the replication specificity of an oncolytic virus based on the function of adenovirus genes that overlap with frequent tumor mutations. It has been shown that mutation in adenovirus E1A can prevent its inactivation of cell cycle-regulator retinoblastoma protein (Rb), and this mutation is the basis of selectivity for an oncolytic adenovirus in clinical trials. However, adenovirus also encodes E4orf6/7, which acts downstream of Rb by activating the cellular transcription factor E2F1 that also drives the cell cycle. We have combined mutations in E1A and E4orf6/7 and discovered highly selective oncolytic adenoviruses that have the promise to be the basis for safe and potent oncolytic cancer therapies.
Author: David T. Curiel
Publisher: Academic Press
ISBN: 0128005106
Category : Science
Languages : en
Pages : 870
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Book Description
Adenoviral Vectors for Gene Therapy, Second Edition provides detailed, comprehensive coverage of the gene delivery vehicles that are based on the adenovirus that is emerging as an important tool in gene therapy. These exciting new therapeutic agents have great potential for the treatment of disease, making gene therapy a fast-growing field for research. This book presents topics ranging from the basic biology of adenoviruses, through the construction and purification of adenoviral vectors, cutting-edge vectorology, and the use of adenoviral vectors in preclinical animal models, with final consideration of the regulatory issues surrounding human clinical gene therapy trials. This broad scope of information provides a solid overview of the field, allowing the reader to gain a complete understanding of the development and use of adenoviral vectors. Provides complete coverage of the basic biology of adenoviruses, as well as their construction, propagation, and purification of adenoviral vectors Introduces common strategies for the development of adenoviral vectors, along with cutting-edge methods for their improvement Demonstrates noninvasive imaging of adenovirus-mediated gene transfer Discusses utility of adenoviral vectors in animal disease models Considers Federal Drug Administration regulations for human clinical trials
Author: Kelly K. Hunt
Publisher: Springer Science & Business Media
ISBN: 159745222X
Category : Medical
Languages : en
Pages : 469
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Book Description
The three sections of this volume present currently available cancer gene therapy techniques. Part I describes the various aspects of gene delivery. In Part II, the contributors discuss strategies and targets for the treatment of cancer. Finally, in Part III, experts discuss the difficulties inherent in bringing gene therapy treatment for cancer to the clinic. This book will prove valuable as the volume of preclinical and clinical data continues to increase.
Author: Stanton L. Gerson
Publisher: Elsevier
ISBN: 0080491367
Category : Science
Languages : en
Pages : 555
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Book Description
The Second Edition of Gene Therapy of Cancer provides crucial updates on the basic science and ongoing research in this field, examining the state of the art technology in gene therapy and its therapeutic applications to the treatment of cancer. The clinical chapters are improved to include new areas of research and more successful trials. Chapters emphasize the scientific basis of gene therapy using immune, oncogene, antisense, pro-drug activating, and drug resistance gene targets, while other chapters discuss therapeutic approaches and clinical applications. This book is a valuable reference for anyone needing to stay abreast of the latest advances in gene therapy treatment for cancer. Provides in-depth description of targeted systems and treatment strategies Explains the underlying cancer biology necessary for understanding a given therapeutic approach Extensively covers immune therapeutics of vaccines, cytokines, and peptide-induced responses Presents translational focus with emphasis on requirements for clinical implementation Incorporates detailed illustrations of vectors and therapeutic approaches ideal for classroom presentations and general reference
Author: Christine E. Engeland
Publisher: Humana
ISBN: 9781493997961
Category : Medical
Languages : en
Pages : 329
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Book Description
This book aims to provide a guide for virologists, translational researchers, and clinicians in the field of cancer research by providing reference protocols and methodologies from vector development through clinical translation. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Oncolytic Viruses: Methods and Protocols aims to ensure successful results in the further study of this vital field.
Author: Institute of Medicine
Publisher: National Academies Press
ISBN: 0309219396
Category : Science
Languages : en
Pages : 570
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Book Description
Many potential applications of synthetic and systems biology are relevant to the challenges associated with the detection, surveillance, and responses to emerging and re-emerging infectious diseases. On March 14 and 15, 2011, the Institute of Medicine's (IOM's) Forum on Microbial Threats convened a public workshop in Washington, DC, to explore the current state of the science of synthetic biology, including its dependency on systems biology; discussed the different approaches that scientists are taking to engineer, or reengineer, biological systems; and discussed how the tools and approaches of synthetic and systems biology were being applied to mitigate the risks associated with emerging infectious diseases. The Science and Applications of Synthetic and Systems Biology is organized into sections as a topic-by-topic distillation of the presentations and discussions that took place at the workshop. Its purpose is to present information from relevant experience, to delineate a range of pivotal issues and their respective challenges, and to offer differing perspectives on the topic as discussed and described by the workshop participants. This report also includes a collection of individually authored papers and commentary.
Author: National Academies of Sciences, Engineering, and Medicine
Publisher: National Academies Press
ISBN: 0309465184
Category : Technology & Engineering
Languages : en
Pages : 189
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Book Description
Scientific advances over the past several decades have accelerated the ability to engineer existing organisms and to potentially create novel ones not found in nature. Synthetic biology, which collectively refers to concepts, approaches, and tools that enable the modification or creation of biological organisms, is being pursued overwhelmingly for beneficial purposes ranging from reducing the burden of disease to improving agricultural yields to remediating pollution. Although the contributions synthetic biology can make in these and other areas hold great promise, it is also possible to imagine malicious uses that could threaten U.S. citizens and military personnel. Making informed decisions about how to address such concerns requires a realistic assessment of the capabilities that could be misused. Biodefense in the Age of Synthetic Biology explores and envisions potential misuses of synthetic biology. This report develops a framework to guide an assessment of the security concerns related to advances in synthetic biology, assesses the levels of concern warranted for such advances, and identifies options that could help mitigate those concerns.
Author: Roland W. Herzog
Publisher: World Scientific
ISBN: 9814280917
Category : Medical
Languages : en
Pages : 415
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Book Description
1. Non-viral gene therapy / Sean M. Sullivan -- 2. Adenoviral vectors / Stuart A. Nicklin and Andrew H. Baker -- 3. Retroviral vectors and integration analysis / Cynthia C. Bartholomae [und weitere] -- 4. Lentiviral vectors / Janka Matrai, Marinee K.L. Chuah and Thierry VandenDriessche -- 5. Herpes simplex virus vectors / William F. Goins [und weitere] -- 6. Adeno-Associated Viral (AAV) vectors / Nicholas Muzyczka -- 7. Regulatory RNA in gene therapy / Alfred. S. Lewin -- 8. DNA integrating vectors (Transposon, Integrase) / Lauren E. Woodard and Michele P. Calos -- 9. Homologous recombination and targeted gene modification for gene therapy / Matthew Porteus -- 10. Gene switches for pre-clinical studies in gene therapy / Caroline Le Guiner [und weitere] -- 11. Gene therapy for central nervous system disorders / Deborah Young and Patricia A. Lawlor -- 12. Gene therapy of hemoglobinopathies / Angela E. Rivers and Arun Srivastava -- 13. Gene therapy for primary immunodeficiencies / Aisha Sauer, Barbara Cassani and Alessandro Aiuti -- 14. Gene therapy for hemophilia / David Markusic, Babak Moghimi and Roland Herzog -- 15. Gene therapy for obesity and diabetes / Sergei Zolotukhin and Clive H. Wasserfall -- 16. Gene therapy for Duchenne muscular dystrophy / Takashi Okada and Shin'ichi Takeda -- 17. Cancer gene therapy / Kirsten A.K. Weigel-Van Aken -- 18. Gene therapy for autoimmune disorders / Daniel F. Gaddy, Melanie A. Ruffner and Paul D. Robbins -- 19. Gene therapy for inherited metabolic storage diseases / Cathryn Mah -- 20. Retinal diseases / Shannon E. Boye, Sanford L. Boye and William W. Hauswirth -- 21. A brief guide to gene therapy treatments for pulmonary diseases / Ashley T. Martino, Christian Mueller and Terence R. Flotte -- 22. Cardiovascular disease / Darin J. Falk, Cathryn S. Mah and Barry J. Byrne
Author: Philippe Fournier
Publisher: Frontiers Media SA
ISBN: 2889194507
Category : Cancer
Languages : en
Pages : 111
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Book Description
Oncolytic viruses (OVs) have emerged as a promising anticancer treatment. OVs selectively infect, replicate in, and kill tumor cells. Oncolytic viral therapy occurs in two phases: an initial phase where the virus mediates direct oncolysis of tumor cells, and a second phase where an induced post-oncolytic immune response continues to mediate tumor destruction and retards progression of the disease. For a long time, the therapeutic efficacy was thought to depend mainly on the direct viral oncolysis based on their tumor selective replication and killing activities. But the post-oncolytic anti-tumor activity induced by the OV therapy is also a key factor for an efficient therapeutic activity. The topic adresses various strategies how to optimize OVs anti-tumor activity.
Author: Igor S Lukashevich
Publisher: Springer
ISBN: 3709118182
Category : Medical
Languages : en
Pages : 393
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Book Description
This book presents a detailed overview of the development of new viral vector-based vaccines before discussing two major applications: preventive vaccines for infectious diseases and therapeutic cancer vaccines. Viral vector-based vaccines hold a great potential for development into successful pharmaceutical products and several examples at the advanced pre-clinical or clinical stage are presented. Nevertheless, the most efforts were focused on novel and very innovative technologies for new generation of vector-based vaccines. Furthermore, specific topics such as delivery and adjuvant and protection strategies for cell-mediated-based vaccines are presented. Given its scope, the book is a “must read” for all those involved in vaccine development, both in academia and industrial vaccine development.
