Treatments from Toxins presents 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.

Features:

• Discusses advances in the field of recombinant botulinum vaccines against all botulinum neurotoxin (BoNT) serotypes.
• Includes an overview of bacterial effector molecules available for the future development of therapeutic options
• Explores the use of endopeptidase domains of the clostridial neurotoxins for the inhibition of stimulated secretions
• Delineates the extensive research and development necessary to comply with regulatory requirements
• Integrates coverage of the structure and mechanisms of action of clostridial neurotoxins with current and emerging applications

Contents

Introduction and Historical Perspective

• Neurotoxigenic Clostridia
• Diseases of Botulinum and Tetanus Neurotoxins
• Clinical Use of Botulinum Neurotoxins

Three-Dimensional protein Structures of Light Chains of Botulinum Neurotoxin Serotypes

• Structure of Botulinum Neurotoxin 150kDa Holotoxin
• Proteolysis of Snare Proteins by Botulinum Neurotoxin Light Chains
• Structure of Botulinum Neurotoxin Serotype A Light Chain
• Structure of Botulinum Neurotoxin Serotype B Light Chain
• A Possible Proteolytic Mechanism of Botulinum Neurotoxins
• Structure of Botulinum Neurotoxin Light Chain E
• Structure of Tetanus Neurotoxin Light Chain

Mechanisms of Actions of Neurotoxins

• Toxin Uptake, Toxicity, and Clinical Disease Manifestation Binding to Nerve Cell Receptors
• Internalization into the Neuronal Cytosol

Vaccines to Protect Against Neurotoxins

• Toxoid Vaccines
• Recombinant Vaccines
• The Vaccine Candidate RBV A/B

Inhibitors of Clostridial Neurotoxin Proteinase Activities

• Inhibitors if Clostridial Neurotoxin Proteinase Activities
• Neutralizing Antibodies

Introduction to Clinical use of Botulinum Neurotoxins

• Theory of Clinical Use
• Practical Aspects of Injection Technique
• Longer Term Side Effects and Problems
• Logistics and Cost
• Dystonia
• Spasticity

Expanding clinical uses of Botulinum Neurotoxins

• New Indications
• The Future: Other Possible Indications and Speculation

Development of Therapeutics Basded Upon Clostridial Endopeptidase Activity

• 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 Relief
• Alternative Therapeutic Possibilities

Use of Neurotoxins as Drug Delivery Systems

• 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

Conclusions and Future Perspectives: Botulinum Neurotoxins as Paradigms for Development of Microbial Effector-Derived Drugs

• To Kill or Not to Kill: Strategies for Toxin Therapeutics
• General Themes for the Future Development of Bacterial Effector-Based Therapeutics

Index

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