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RNA Therapeutics
The Evolving Landscape of RNA Therapeutics
1st Edition - April 10, 2022
Editors: Paloma H. Giangrande, Vittorio de Franciscis, John J. Rossi
Language: English
Paperback ISBN:9780128215951
9 7 8 - 0 - 1 2 - 8 2 1 5 9 5 - 1
eBook ISBN:9780128217399
9 7 8 - 0 - 1 2 - 8 2 1 7 3 9 - 9
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 incre…Read more
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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.
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
Active researchers in biochemistry, human genetics, molecular biology, cell biology, pharmacology; researchers in industry and pharma. Students of biochemical sciences; clinicians across disease specialties
Cover image
Title page
Table of Contents
Copyright
Contributors
Section 1: The world of RNA therapeutics: Available RNA tools to modulate cellular processes
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
No. of pages: 472
Language: English
Edition: 1
Published: April 10, 2022
Imprint: Academic Press
Paperback ISBN: 9780128215951
eBook ISBN: 9780128217399
PG
Paloma H. 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
Vd
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
JR
John J. Rossi
Affiliations and expertise
City of Hope's Beckman Research Institute, Duarte, California, U.S.A.