Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development
Abstract
:1. Introduction
2. Overview of Current Therapeutic Applications
Year | Author/Institution | Botulinum Toxin, Commercial Designation | |
---|---|---|---|
1822 | Justinus Kerner | Sausage poison (first envisioned possible therapeutic use) | |
1870 | Müller | Botulism (Latin: botulus) for sausage | |
1895 | Van Ermengem | Clostridium botulinum (causative agent of botulism) | |
1919 | G.S. Burke | Determination of minimum lethal dose in guinea pigs | |
1928 | Herman Sommer | BoNT (purified) isolation | |
1946 | Carl Lamanna Edward Schantz | LD50 test: neurotoxin activity BoNT/A in crystalline form | |
1949 | Arnold Burgen | Neuromuscular transmission blockade | |
1950 | Vernon Brooks | BoNT/A: blockade of acetylcholine from motor nerve endings | |
1960s | Schantz/Scott | Strabismus: monkeys | |
1980 | Scott | Strabismus: humans | |
1986 | Joseph Jankovic | Placebo controlled trial of BoNT/A in blepharospasm and cervical-cranial dystonia | |
1987 | Drs. Jean and Alastair Carruthers | Cosmetic benefits of BoNT/A found accidentally by ophthalmologists treating patients for involuntary blinking | |
1988 | Allergan | Oculinum (BoNT/A): clinical trials | |
1993 | Montecucco and Schiavo | SNAP-25, molecular target of botulinum toxin type A | |
1995 | MHRA | Approves Dysport® (abobotulinumtoxinA, Ipsen)(~5 ng/500 mouse LD50) for strabismus in UK | |
2000 | FDA | Approves Botox® (onabotulinumtoxinA, Allergan) for cervical dystonia | |
2001 | Botox® approval for cosmetic procedures in Canada and New Zealand Approves first type B toxin, NeuroBloc® for cervical dystonia | ||
2002 | FDA | Approves Botox® for cosmetic therapy (Australia, Switzerland, Taiwan, and Singapore) | |
2003 | AFSSAPS | Approves Botox as Vistabel® (France) | |
2003 | FDA | Approves Myobloc® (rimabotulinumtoxinB, Solstice Neuroscience) for cervical dystonia Neurobloc® | |
2004 | FDA | Approves Botox® for primary axillary hyperhidrosis (severe underarm sweating) | |
2006 | MHRA | Approves Botox as Vistabel® for treatment of glabellar lines | |
2006 | - | Xeomin® (incobotulinumtoxinA, Merz) licensed in Germany for blepharospasm and cervical dystonia in adults | |
2006 | Korean FDA | Neuronox® (Medy-Tox) approval for blepharospasm | |
2009 | MHRA FDA | Approves Azzalure® for treatment of glabellar lines approves Dysport® for glabellar lines and cervical dystonia | |
2010 | FDA | Approves Botox® to treat chronic migraine, adult upper limb spasticity, and specific form of urinary incontinence Approves Xeomin® for cervical dystonia and blepharospasm | |
2011 | FDA | Approves Xeomin® to treat bladder detrusor over-activity in patients with neurologic conditions | |
2011 | FDA | Approves Xeomin® (incobotulinumtoxinA) as Bocouture® for glabellar lines in adult patients | |
2012 | NHS UK | Approves Botox® to treat chronic migraine | |
2013 | Korea FDA | Approves Nabota® (Daewoongs Pharmaceuticals) approves Botox® for overactive bladder and lateral canthal lines | |
2014 | China | BoNT/A product also approved as Lantox® and Prosigne® (Lanzhou Institute of Biological Products, China) | |
2015 | FDA | FDA Approval of Xeomin® (incobotulinumtoxinA) and Dysport® (AbobotulinumtoxinA) for adult upper limb spasticity | |
2017 | Approval of Botox® and Dysport® to treat adult lower limb spasticity and Dysport® only to treat children lower limb spasticity | ||
2018 | FDA | FDA approves Xeomin® for sialorrhea Nabota® (Korea 2014) approved by FDA in 2019 Distributed in USA since 2018 as Jeuveau® | |
2019 | FDA | Approves Botox® for pediatric upper limb spasticityApproves Jeuveau® for glabellar lines |
3. Exploration of Therapeutic Potential of Novel Toxinotypes or Subtypes and Modified Botulinum neurotoxins (BoNTs)
3.1. Differential Effects of Toxinotypes and New Subtypes
3.2. Bioengineered BoNTs for Long Duration of Effect
3.3. Bioengineered BoNTs for Increased Activity in Humans
3.4. Bioengineered BoNTs for Targeting Sensory Neurons and Treatment of Pain
BoNT | Modification | Application | Reference |
---|---|---|---|
BoNTs | Re-engineering of target specificity | Chronic pain | [98] |
BoTIMs | Full-length BoNTs incorporation inactive LC/A and LC/E | Prolonged effect in various pain states including chronic pain | [55,90,99] |
BoNT/BMY | Mutations enhancing binding to human synaptotagmin-II, mutations of the lipid binding loop | Enhanced efficacy | [60,65,67,100] |
LC/B | Mutations of substrate recognition pockets | Novel therapy to escape immunoresistance in BoNT/B therapy. | [61] |
BoNT/LC | LC Mutations | Maintain cleavage of syntaxin | [64,101] |
BoNT/B TM (triple mutant) | Mutations inducing protonation of residues involved in translocation process | Increased neurotoxicity due to faster cytosolic delivery of the enzymatic domain | [66] |
BoNT/A | Protein stapling allowing BoNT/A re-assembly in situ | Development of neuronal modulating agents | [87] |
BoNT/A and E chimera | Chimera construction | Targeting specific populations of neurons or secretory cells | [89] |
BoNT/LC | Vector-expressed transgenic BoNT/LC | Stable, selective, and controllable, BoNT/LC expression in different neuron types | [97] |
BoNTs | Ligation to agents targeting BoNT delivery into specific cell types | Pain relief, inflammation and neuropathic pain | [88] |
4. Harnessing BoNTs to Retarget Non-Neuronal Territories
5. Production of Inactive BoNT Holoprotein for Vaccines Development
BoNT Sub-Unit | Applications | References |
---|---|---|
LHN fragments from BoNT/A and B | Single-dose protection against BoNT/A1, A2, and A3 and against BoNT/B1and B4 (nonproteolytic) | [118] |
rBV A/B recombinantly derived from the non-toxic C-terminal domains of BoNT/A1 and BoNT/B1 | Protection against BoNT/A1 and BoNT/B1 | [119] |
Recombinant BoNT A HC, BoNT B HC, BoNT C HC, BoNT D HC,) BoNT E HC, and BoNT F HC produced in Pichia pastoris | Protection against BoNT/A, B, C, D, E, and F respectively | [122,125,130,131,132,133,134,135,136] |
ciBoNT/A1 HP ciBoNT HPs | Protective immunity against the BoNTs variants | [126,137] |
BoNT/A1 LC–HN | Protection against BoNT/A1, A2, and A3 | [129] |
BoNT/A1 LC–HN+HC | Protection against BoNT/A | [138] |
Multivalent HC/A, HC/B, and HC/E vaccine | Protection against BoNT/A, B, and E | [127] |
6. Future Approaches and Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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BoNT | Modification | Application | Reference |
---|---|---|---|
LC-HN fragment | Targeted delivery | Deliver LC into cells not naturally targeted by BoNT | [100] |
LC-HN/A | Coupling to lectin wheat germ agglutinin | Inhibit noradrenaline release | [107] |
TSIs: targeted secretion inhibitors or TVEMP | LC domain (SNARE cleavage capability) HN domain (intracellular translocation) binding domain a peptide interacting with target cell | Treatment of pain, endocrine disease (acromegaly) and cancer | [35,110] |
LC-HN part of BoNT | LC-HN coupled to epidermal growth factor (LC-HN-EGF) | [96,117] | |
BoNT/E LC | Mutations | Cleave human SNAP-23 for treatment of asthma or hypersecretions | [112] |
BoNT/A | Protein stapling technology | Neuroscience research and future medical applications in chronic pain | [87] |
BoNT/E | Mutation of LC | inhibition of interleukin-8 (IL-8) and mucin release | [111] |
BoNT/C | Mutations of C2 binding/translocation domain | delivery of therapeutics to peripheral neurons | [115] |
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Rasetti-Escargueil, C.; Popoff, M.R. Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development. Toxins 2021, 13, 1. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13010001
Rasetti-Escargueil C, Popoff MR. Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development. Toxins. 2021; 13(1):1. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13010001
Chicago/Turabian StyleRasetti-Escargueil, Christine, and Michel R. Popoff. 2021. "Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development" Toxins 13, no. 1: 1. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13010001