Engineering of Botulinum Neurotoxins for Biomedical Applications

Webb, Robert

doi:10.3390/toxins10060231

Cited by 32 publications

(29 citation statements)

References 91 publications

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“…In contrast, other serotypes of botulinum toxin enter the neuron via a set of membrane receptors called synaptotagmins and target different SNARE proteins such as VAMP (synaptobrevin) and syntaxin to cause chemodenervation 34 . Research involving the use of recombinant and chimeric toxins (eg, part A toxin and part B toxin) to improve clinical efficacy is ongoing 35 …”

Section: Postulate Imentioning

confidence: 99%

The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: Key Clinical Postulates II

Nestor

Arnold

Fischer

2020

J of Cosmetic Dermatology

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Background The literature on botulinum neurotoxin type A (BoNT‐A) is extensive, often contradictory, and confounded by a competitive market of products and research attempting to distinguish brand individuality. Methods A comprehensive review of literature on the principles of BoNT‐A in aesthetics as well as clinical examples. Results In 2017, the Eight Key Clinical Postulates were formulated as a guide for the aesthetic practitioner in understanding BoNT‐A pharmacodynamics and to compare different toxins. These are now updated to include (a) All type A toxins act identically; (b) The mathematical relationship between toxin and receptor is the basis of efficacy, and clinical efficacy is influenced by molecular potency and patient attributes including muscle mass, gender, age, and ethnicity; (c) Efficacy, onset, and duration are functions of “molecular potency” defined as the number of active 150 kDa molecules available for binding; (d) “Molecular potency” is difficult to objectively quantify for commercially available toxins; (e) Up to a point, increased molecular potency decreases time to onset and increases duration of effect, and the “Molecular Potency Quotient” is a construct for comparing molecular potency commercial cost; (f) The area of effect of a toxin injection is dependent upon molecular potency, diffusion (passive), and spread (active); (g) Differing reconstitution volumes; and (h) Increased number of injection sites can affect spread, onset, and duration of effect. Conclusions The principles of BoNT‐A use in aesthetics are complex yet understandable as outlined in the framework of the updated Eight Key Clinical Postulates and serves as a useful tool for providing the most effective treatment and interpreting research on present and future toxin formulations.

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Section: Postulate Imentioning

confidence: 99%

The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: Key Clinical Postulates II

Nestor

Arnold

Fischer

2020

J of Cosmetic Dermatology

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“…BoNTs are categorized into 7 canonical antigenic serotypes (A-G) and further stratified into over 40 subtypes based on primary sequence divergence (3). The therapeutic challenge presented by this diversity is compounded by the ongoing discovery of noncanonical serotypes and subtypes with unknown toxicokinetic properties, as well as genetic engineering of existing toxins to introduce capabilities (4). BoNT has a characteristic heterodimeric protein structure consisting of a 100-kDa heavy chain (HC) and 50-kDa light chain (LC), which are associated through a disulfide bond.…”

Section: Introductionmentioning

confidence: 99%

Symptomatic treatment of botulism with a clinically approved small molecule

Vazquez-Cintron¹,

Machamer²,

Ondeck³

et al. 2020

JCI Insight

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“…BoNTs are also important and widely used pharmaceuticals. Used in small doses and applied locally by intramuscular injection, BoNTs can provide long-lasting relief to many neurologic disorders, including dystonias, spasticity, pain, and many other applications, including cosmesis [1][2][3][4][5]. However, only 10-fold higher doses than the highest-used therapeutic doses are estimated to be lethal to humans if injected intravenously.…”

Section: Introductionmentioning

confidence: 99%

Critical Analysis of Neuronal Cell and the Mouse Bioassay for Detection of Botulinum Neurotoxins

Pellett

Tepp

Johnson

2019

Toxins

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Botulinum Neurotoxins (BoNTs) are a large protein family that includes the most potent neurotoxins known to humankind. BoNTs delivered locally in humans at low doses are widely used pharmaceuticals. Reliable and quantitative detection of BoNTs is of paramount importance for the clinical diagnosis of botulism, basic research, drug development, potency determination, and detection in clinical, environmental, and food samples. Ideally, a definitive assay for BoNT should reflect the activity of each of the four steps in nerve intoxication. The in vivo mouse bioassay (MBA) is the 'gold standard' for the detection of BoNTs. The MBA is sensitive, robust, semi-quantitative, and reliable within its sensitivity limits. Potential drawbacks with the MBA include assay-to-assay potency variations, especially between laboratories, and false positives or negatives. These limitations can be largely avoided by careful planning and performance. Another detection method that has gained importance in recent years for research and potency determination of pharmaceutical BoNTs is cell-based assays, as these assays can be highly sensitive, quantitative, human-specific, and detect fully functional holotoxins at physiologically relevant concentrations. A myriad of other in vitro BoNT detection methods exist. This review focuses on critical factors and assay limitations of the mouse bioassay and cell-based assays for BoNT detection. Key Contribution:This manuscript reviews two widely used botulinum neurotoxin detection assays, the mouse bioassay and cell-based assays, and the critical factors involved in their methodology as well as interpretation of results. Despite our ability to now reduce animal use and replace the mouse bioassay for certain aspects of botulinum neurotoxin detection, the mouse bioassay is sensitive and is the only in vivo assay considering all aspects of botulinum neurotoxin intoxication on a physiological level as well as pharmacokinetic aspects of the toxins, and thus remains important assay for botulinum neurotoxin detection.Toxins 2019, 11, 713 2 of 23 cells, with preferential entry into motor-neurons. Inside a neuron, the toxins block neurotransmitter release, leading to the long-lasting descending bilateral paralysis characteristic of botulism [6]. Even if applied intramuscularly for therapeutic purposes, a portion of the injected BoNTs, in particular at high doses, can diffuse away from the local injection site leading to distal neuronal effects and at very high doses systemic distribution [7][8][9][10]. BoNTs can also enter human or vertebrate circulation and cause botulism by different routes, including ingestion of contaminated foods, by wound infection with neurotoxigenic clostridia, and by the colonization of the intestinal tract by neurotoxigenic clostridia, causing infant botulism or adult intestinal botulism [11,12]. The latter is rare, as C. botulinum usually does not colonize a healthy intestine with a mature microbiota. The severe symptoms of botulism last from several days to up to a year, depending ...

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Engineering of Botulinum Neurotoxins for Biomedical Applications

Cited by 32 publications

References 91 publications

The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: Key Clinical Postulates II

The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: Key Clinical Postulates II

Symptomatic treatment of botulism with a clinically approved small molecule

Critical Analysis of Neuronal Cell and the Mouse Bioassay for Detection of Botulinum Neurotoxins

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