1st Edition
Treatments from Toxins The Therapeutic Potential of Clostridial Neurotoxins
As little as two decades ago, deliberately injecting botulinum toxin into patients would have seemed foolhardy at best and criminal at worst. The increased clinical use of botulinum toxins has expanded the body of knowledge available on the structure and function of these proteins. This knowledge can be applied to topics as varied as therapies based on the endopeptidase activity of the toxins, vaccine development, protection against botulism, and vectors for neuronal drug delivery. Based on recent scientific and clinical information from top international authorities, Treatments from Toxins: The Therapeutic Potential of Clostridial Neurotoxins reviews the status of current research and development and identifies significant developments.
Drawing on their vast experience in this field, the editors present the basic background of the bacteriology and genetics of the neurotoxigenic clostridia, a history of the discovery of the neurotoxins, and an overview of the tetanus and botulism diseases. The chapters detailing common medical applications of the toxins cover side effects and novel uses, including neuronal drug delivery strategies, and provide a fresh look at what can still be achieved. They also explore the toxins as potential threat agents and the advent of the therapeutic use of botulinum toxins. Highlighting the pitfalls, successes, and challenges that exist when engineering complex proteins, the book brings together the clinical and theoretical worlds. It presents a broad overview of the current status of botulinum research and its clinical applications.
Introduction
Neurotoxigenic Clostridia
Diseases of Botulinum and Tetanus Neurotoxins
Clinical Use of Botulinum Neurotoxins
THREE-DIMENSIONAL PROTEIN STRUCTURES OF LIGHT CHAINS OF BOTULINUM NEUROTOXIN SEROTYPES A, B, AND E AND TETANUS NEUROTOXIN, S. Swaminathan and R.C. Stevens
Structure of Botulinum Neurotoxin 150kDa Holotoxin
Proteolysis of Snare Proteins by Botulinum Neurotoxin Light Chains
Structure of Botulinum Neurotoxin Serotype A Light Chain
Strucuture of Botulinum Neurotoxin Serotype B Light Chain
A Possible Proteolytic Mechanism of Botulinum Neurotoxins
Strudture of Botulinum Neurotoxin Light Chain E
Structure of Tetanus Neurotoxin Light Chain
Conclusion
References
MECHANISMS OF ACTIONS OF NEUROTOXINS, H. Bigalke and T. Binz
Introduction
Toxin Uptake, Toxicity, and Clinical Disease Manifestation
Binding to Nerve Cell Receptors
Internalization into the Neuronal Cytosol
References
VACCINES TO PROTECT AGAINST NEUROTOXINS, L.A. Smith and I. Henderson
Introduction
Toxoid Vaccines
Recombinant Vaccines
The Vaccine Candidate RBV A/B
Conclusion
References
INHIBITORS OF CLOSTRIDIAL NEUROTOXIN PROTEINASE ACTIVITIES, J.J. Schmidt and K.A. Foster
Inhibitors if Clostridial Neurotoxin Proteinase Activities
Neutralizing Antibodies
Conclusion
References
INTRODUCTION TO CLINICAL USE OF BOTULINUM NEUROTOXINS, M.P. Barnes
Introduction
Theory of Clinical Use
Practical Aspects of Injection Technique
Longer Term Side Effects and Problems
Logistics and Cost
Dystonia
Spasticity
Conclusions
References
EXPANDING CLINICAL USES OF BOTULINUM NEUROTOXINS, A.P. Moore
Introduction
New Indications
The Future: Other Possible Indications and Speculation
Conclusions
DEVELOPMENT OF THERAPEUTICS BASED UPON CLOSTRIDIAL ENDOPEPTIDASE ACTIVITY, K.A. Foster and J.A. Chaddock
Introduction
Clostridial Neurotoxin Structure and Function: The 'Endopeptidase' Domain
Recombinant Expression of the LHN/A
Rationale for Use of the LHN Endopeptidase
Pain
The Potential Use of Neurotoxins Endopeptidase Fragments for Pain Releif
Alternative Therapeutic Possibilities
Conclusions
References
USE OF NEUROTOXINS AS DRUG DELIVERY SYSTEMS, P. Foran
Overview
Generation of Non-Toxic Derivatives Retaining Neuronal Targeting and Delivery Capabilities Using Classical Biochemical Mehtods or Recombinant Means
The Diverse Neuronal Targeting and Cell Trafficking Pathways Exerted by Clostridial Neurotoxins
In Vitro or In Vivo Neuronal Targeting Achievements Made Using Innocuous Derivatives: But Not Demonstrating Cytosolic Transfer
Achievements of Cell or Neuronal Targeting, as well as, Cytoplasmic Delivery of Foreign Cargos Using Innocuous Derivatives
Important Structural Features Proven Essential For Efficient In Vivo Neuronal Targeting and Cytoplasmic Delivery of Cargo
Strategies for the Efficient Linkage of Therapeutic Adducts to Transporters: Approaches that Ensure Optimal Linkage Efficiency and Orientation
Potential Diseases that May be Targeted Using Innocuous BoNT- or TeNT-based Neuron Delivery Vehicles
How Much Cargo can BoNT-Based Transporters Deliver?
The Varied Intracellular Trafficking and Site-Specific Delivery Addresses Anticipated for Cargos Linked to BoNT-or TeNT-based Vehicles
Conclusion
References
CONCLUSIONS AND FUTURE PERSPECTIVES: BOTULINUM NEUROTOXINS AS PARADIGMS FOR DEVELOPMENT OF MICROBIAL EFFECTOR-DERIVED DRUGS, J.M. Sutton
Introduction
To Kill or Not to Kill: Strategies for Toxin Therapeutics
General Themes for the Future Development of Bacterial Effector-Based Therapeutics
References
Index
Biography
Keith Alan Foster, Peter Hambleton, Clifford C. Shone
