RNA Therapeutics

RNA Therapeutics

The Evolving Landscape of RNA Therapeutics

1st Edition - April 10, 2022

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  • Editors: Paloma Giangrande, Vittorio de Franciscis, John Rossi
  • Paperback ISBN: 9780128215951
  • eBook ISBN: 9780128217399

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Description

RNA Therapeutics: The Evolving Landscape of RNA Therapeutics provides a comprehensive overview of RNA therapeutic modalities, from bench-to-bedside, with an emphasis on the increasingly impactful areas of gene therapy, oligonucleotide therapeutics, gene editing and delivery. International leaders in the field examine RNA-based therapeutics tools that have been developed to-date to modulate cellular processes such as transcription, translation and protein function. Approved RNA-based therapies and lessons learned from failed therapies are discussed in-depth, as are evolving advances in RNA biochemical analysis, and similar advances that are enabling clinical application of RNA-based therapies. Later sections discuss delivery technologies, remaining hurdles in research and translation, the therapy development process from the lab to the clinic, and novel RNA-based therapies currently in development.

Key Features

  • Features leading experts in the field of RNA therapeutics, spanning all classes of RNA therapies
  • Provides a detailed examination of approved RNA therapies and lessons learned from failed therapeutics
  • Covers all aspects of therapeutic discovery and preclinical development, as well as clinical translation, manufacturing and regulatory aspects

Readership

Active researchers in biochemistry, human genetics, molecular biology, cell biology, pharmacology; researchers in industry and pharma. Students of biochemical sciences; clinicians across disease specialties

Table of Contents

  • Cover image
  • Title page
  • Table of Contents
  • Copyright
  • Contributors
  • Section 1: The world of RNA therapeutics: Available RNA tools to modulate cellular processes
  • Chapter 1: Targeting chromatin: Transcriptional gene activation (saRNA)
  • Abstract
  • Discovery and mechanism of action
  • Preclinical therapeutic saRNA proof-of-concept studies
  • Clinical-stage therapeutic saRNA
  • Conclusions
  • References
  • Chapter 2: Argonaute and TNRC6, partners in RNAi
  • Abstract
  • Introduction
  • Argonaute protein
  • TNRC6 protein
  • Tools for analyzing AGO and TNRC6 function
  • Conclusion
  • References
  • Chapter 3: Targeted RNA therapeutics for treatment of cancer and immunomodulation
  • Abstract
  • Acknowledgments
  • Lipophilic oligonucleotide conjugates
  • Oligonucleotides conjugated with receptor ligands
  • Antibody-oligonucleotide conjugates as a delivery strategy
  • DNA/RNA aptamers for targeted delivery of oligonucleotide therapeutics
  • Oligonucleotide immunotherapeutics targeted to endosomal TLR9
  • Conclusion and perspectives
  • References
  • Chapter 4: Extrahepatic delivery of RNA to immune cells
  • Abstract
  • Acknowledgments
  • Introduction
  • RNA-bio-conjugates for therapeutic and immune cell intervention
  • Supermolecular nanocarriers that manage to deliver RNA to leukocytes for immune cell manipulation
  • Discussion
  • References
  • Section 2: Learning from history
  • Chapter 5: Aptamer-based protein inhibitors
  • Abstract
  • Aptamers as a novel type of protein inhibitors
  • Current aptamer-based protein inhibitors for therapeutic application
  • Challenges and advances for aptamer development targeting circulating proteins
  • Recent advances and future directions of aptamer-based protein inhibitors
  • Conclusion
  • References
  • Chapter 6: Lessons learned from developing an oligonucleotide drug for a rare disease
  • Abstract
  • Introduction
  • Preclinical studies to select a compound for trials
  • Preclinical screening of candidate AOs
  • Chemistry, which chemistry?
  • Planning a clinical trial for a pediatric rare disease
  • Results
  • Conclusions
  • References
  • Section 3: Delivery
  • Chapter 7: Nucleoside modifications of in vitro transcribed mRNA to reduce immunogenicity and improve translation of prophylactic and therapeutic antigens
  • Abstract
  • Introduction
  • Nucleic acids and innate immunity
  • Discrimination between endogenous and exogenous RNA
  • Origins of the immunogenicity of in vitro transcribed RNA
  • Strategies to decrease RNA immunogenicity and improve the translation of in vitro transcribed mRNA sequences
  • Conclusion and future perspective
  • References
  • Chapter 8: SOMAmer reagents and the SomaScan platform: Chemically modified aptamers and their applications in therapeutics, diagnostics, and proteomics
  • Abstract
  • Acknowledgments
  • Introduction
  • The advent of SOMAmer reagent technology
  • Development of aptamers for therapeutic applications
  • The future of aptamer therapeutics
  • Development of an aptamer-based proteomics platform
  • Other proteomic technologies
  • Specificity and selectivity of the SomaScan platform
  • Proteomics discovery on the SomaScan platform
  • From comprehensive proteomic profiling to a liquid health check
  • Closing remarks
  • References
  • Section 4: From bench to bedside
  • Chapter 9: CMC and regulatory aspects of oligonucleotide therapeutics
  • Abstract
  • Acknowledgments
  • Introduction
  • Major classes of RNA therapeutics
  • Approved oligonucleotide therapeutics to date
  • Most common modifications in therapeutic ONs
  • Modification of the internucleotide linkage
  • Conjugation strategies
  • Modifications of the sugar
  • Modification of the nucleobases
  • Identification and control of impurities
  • Impurity classification
  • Conclusions
  • References
  • Further reading
  • Chapter 10: CMC: Regulatory landscape
  • Abstract
  • Introduction
  • IND module 3—Quality: Content
  • Drug substance
  • Drug product
  • Placebo
  • Conclusion: Some take-home messages
  • Informal FDA guidance regulator
  • European guideline
  • References
  • Chapter 11: CMC and manufacturing
  • Abstract
  • Definitions
  • Introduction
  • Quality principles
  • Project life cycle prior to entering the regulated pathway
  • Manufacturing process development
  • Starting materials, material needs, and scale-up
  • Chemistry, manufacturing and controls for phase I
  • Lifecycle management
  • References
  • Section 5: From bench to bedside
  • Chapter 12: RNA delivery for cancer gene therapy
  • Abstract
  • Introduction
  • The RNA delivery strategies
  • Ligand-mediated RNA delivery
  • CRISPR/Cas9-mediated gene therapy
  • Emerging RNA-based gene therapies
  • Modalities to increase pharmacodynamics, pharmacokinetics, bioavailability, and biodistribution of RNA delivery systems
  • Extrahepatic delivery: Challenges and novel approaches
  • Conclusions
  • References
  • Further reading
  • Chapter 13: Combinatorial RNA therapies in cancer immunotherapy: Challenges and directions
  • Abstract
  • Introduction
  • Combinatorial RNA therapies with aptamer
  • Additional applications of aptamers
  • Other combinatorial RNA therapeutics for cancer
  • Emerging RNA therapeutics
  • Challenges
  • Conclusion
  • References
  • Index

Product details

  • No. of pages: 472
  • Language: English
  • Copyright: © Academic Press 2022
  • Published: April 10, 2022
  • Imprint: Academic Press
  • Paperback ISBN: 9780128215951
  • eBook ISBN: 9780128217399

About the Editors

Paloma Giangrande

Dr. Paloma Giangrande is the VP of Biology at Wave Life Sciences, Cambridge, MA and Adjunct Associate Professor of Internal Medicine at the University of Iowa, Iowa City, IA. Her career has been dedicated to the investigation and development of RNA-based therapeutic approaches (including RNA aptamers, siRNAs, and mRNA) for cancer, cardiovascular disease, rare diseases, and critical illness. As a consequence, she has developed a deep understanding of these technologies, diseases, and associated disease mechanisms. She is also an internationally recognized expert in oligonucleotide therapeutics and delivery. Towards this end, she was the first to demonstrate that RNA ligands (aptamers) can be used to deliver therapeutic siRNAs to target cells. Her 60+ publications and 9+ patents are a testament to this body of work and her commitment to the development of novel RNA-based therapies for many diseases.

Affiliations and Expertise

Associate Professor of Internal Medicine, University of Iowa, Iowa City, IA; Director Rare Diseases, ModernaTx Inc, Cambridge, MA, USA

Vittorio de Franciscis

Dr. Vittorio de Franciscis is Senior Collaborator at the CNR Institute of Genetic and Biomedical Research (IRGB) in Milan Italy. For more than ten years, the interest of the research has focused on translating the understanding of the molecular basis of neoplastic transformation in the design of selective therapies based on the use of therapeutic RNAs (aptamers, siRNAs, miRNAs). In his laboratory, they demonstrated the possibility of generating aptamers that bind to high affinity and inhibit transmembrane receptors involved in cancer progression (including, EGFR, AXL, PDGFR, IR, Eph). For the selection of aptamers they have developed a variant of the SELEX technology that makes use of living cells as a complex target. They have recently shown that such RNA aptamers against RTK can be used as targeting moieties for the selective delivery of therapeutic miRNAs and anti-miRs, against tumor cells and tissues.

Affiliations and Expertise

Senior Collaborator, Research Director, CNR, Institute of Experimental Endocrinology and Oncology, Naples, Italy

John Rossi

Dr. John J. Rossi is Lidow Family Research Endowed Chair and Professor in the Dept. of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope. He currently serves as the Morgan and Helen Chu Dean’s Chair, and Dean of Irell & Manella Graduate School of Biological Sciences. He served as an Associate Director of Laboratory Research – City of Hope Comprehensive Cancer Center for City of Hope. He joined City of Hope, Inc. (COH) in 1980 as an Assistant Research Scientist in the Department of Molecular Genetics. He was Chairman of the Division of Biology in 1992. In 1993, COH bestowed its highest honor upon him by naming him to its Gallery of Medical and Scientific Achievement for his pioneering work at the molecular level in the battle against AIDS and other major diseases.

Affiliations and Expertise

Professor and Chairman, Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope Monrovia Biomedical Research Center, Monrovia, CA, USA

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