Neuronal delivery of antibodies has therapeutic effects in animal models of botulism

McNutt, Patrick; Vazquez-Cintron, Edwin; Tenezaca, Luis; Ondeck, Celinia A.; Kelly, Kyle E.; Mangkhalakhili, Mark; Machamer, James B.; Angeles, Christopher A.; Glotfelty, Elliot J.; Cika, Jaclyn; Benjumea, Cesar H.; Whitfield, Justin T.; Band, Philip A.; Shoemaker, Charles B.; Ichtchenko, Konstantin

doi:10.1126/scitranslmed.abd7789

Cited by 27 publications

(32 citation statements)

References 47 publications

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“…To date, only a few publications have shown beneficial treatment of botulism with experimental INABDs [21,[27][28][29][30][31][32][33][34]. Due to the absence of approved INABDs, the proof of concept of our model, in terms of measuring the beneficial effects of potential anti-BoNT/A compounds, was assessed by pharmaceutical antitoxin.…”

Section: Discussionmentioning

confidence: 99%

A Rabbit Model for the Evaluation of Drugs for Treating the Chronic Phase of Botulism

Torgeman

Diamant

Dor

et al. 2021

Toxins

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Antitoxin, the only licensed drug therapy for botulism, neutralizes circulating botulinum neurotoxin (BoNT). However, antitoxin is no longer effective when a critical amount of BoNT has already entered its target nerve cells. The outcome is a chronic phase of botulism that is characterized by prolonged paralysis. In this stage, blocking toxin activity within cells by next-generation intraneuronal anti-botulinum drugs (INABDs) may shorten the chronic phase of the disease and accelerate recovery. However, there is a lack of adequate animal models that simulate the chronic phase of botulism for evaluating the efficacy of INABDs. Herein, we report the development of a rabbit model for the chronic phase of botulism, induced by intoxication with a sublethal dose of BoNT. Spirometry monitoring enabled us to detect deviations from normal respiration and to quantitatively define the time to symptom onset and disease duration. A 0.85 rabbit intramuscular median lethal dose of BoNT/A elicited the most consistent and prolonged disease duration (mean = 11.8 days, relative standard deviation = 27.9%) that still enabled spontaneous recovery. Post-exposure treatment with antitoxin at various time points significantly shortened the disease duration, providing a proof of concept that the new model is adequate for evaluating novel therapeutics for botulism.

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Section: Discussionmentioning

confidence: 99%

A Rabbit Model for the Evaluation of Drugs for Treating the Chronic Phase of Botulism

Torgeman

Diamant

Dor

et al. 2021

Toxins

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“…All BoNTs have a catalytic light chain (LC), which is a Zn 2+ -endopeptidase that specifically cleaves neuronal SNARE proteins and is mainly responsible for BoNT’s neurotoxic effects, while the heavy chain (HC) mediates toxin attachment to neurons and delivers the LC into the cytosol. Two recent reports demonstrated that animals with symptomatic botulism can be rescued by treatments with biomolecular antidotes consisting of an atoxic BoNT delivery vehicle fused to VHHs that bind and inhibit the LC of the intoxicating BoNT [ 9 , 10 ]. These findings suggest that more effective botulism antidotes will be possible with the identification of VHHs possessing higher potency to inhibit the LC of BoNT, particularly those that are broadly active on most or all natural subtypes of each BoNT serotype.…”

Section: Introductionmentioning

confidence: 99%

Probing the structure and function of the protease domain of botulinum neurotoxins using single-domain antibodies

et al. 2022

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Botulinum neurotoxins (BoNTs) are among the deadliest of bacterial toxins. BoNT serotype A and B in particular pose the most serious threat to humans because of their high potency and persistence. To date, there is no effective treatment for late post-exposure therapy of botulism patients. Here, we aim to develop single-domain variable heavy-chain (VHH) antibodies targeting the protease domains (also known as the light chain, LC) of BoNT/A and BoNT/B as antidotes for post-intoxication treatments. Using a combination of X-ray crystallography and biochemical assays, we investigated the structures and inhibition mechanisms of a dozen unique VHHs that recognize four and three non-overlapping epitopes on the LC of BoNT/A and BoNT/B, respectively. We show that the VHHs that inhibit the LC activity occupy the extended substrate-recognition exosites or the cleavage pocket of LC/A or LC/B and thus block substrate binding. Notably, we identified several VHHs that recognize highly conserved epitopes across BoNT/A or BoNT/B subtypes, suggesting that these VHHs exhibit broad subtype efficacy. Further, we identify two novel conformations of the full-length LC/A, that could aid future development of inhibitors against BoNT/A. Our studies lay the foundation for structure-based engineering of protein- or peptide-based BoNT inhibitors with enhanced potencies and cross-subtypes properties.

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“…Several studies reported that, after this toxin consumed and absorbed in the intestines would be visible muscle paralysis in the respiratory and cardiac system, suffocation, heart failure, and death, the mortality rate is between 30% and 60% [33][34][35][36]. It has been shown that botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in suffocation [37]. Gastrointestinal symptoms are common in food botulism (nausea, vomiting, abdominal pain, diarrhea, dry mouth) and may precede neurological syndromes [38].…”

Section: Resultsmentioning

confidence: 99%

Epidemiological aspects of poisoning Infectious-toxic bacteria of botulism on food poisoning in Iran; A review study

Mirbehresi

Pirhadi

Shokri

et al. 2022

Egyptian Journal of Veterinary Sciences

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B OTULISM is a rare neuroparalytic syndrome, caused by a neurotoxin produced by bacteria of the genus Clostridium. Signs and symptoms of food botulism begin 12 to 36 hours after the toxin enters the bloodstream .Clostridium botulinum is one of the most common life-threatening agents worldwide, producing the botulinum neurotoxin (BoNT). Poisoning is caused by the consumption of a highly toxic exotoxin produced during the growth of microorganisms in food. The growth of Clostridium botulinum strains and their production of toxins in vacuum processed foods have received special attention. Symptoms of botulism may appear 12 to 72 hours after eating foods that contain toxins, such as canned tuna, local dairy products, and home-made or commercial foods. Symptoms of poisoning include nausea, vomiting, bruising, dizziness and headache, dry skin, sore throat, constipation, mild fever (or no fever), muscle paralysis, diplopia, and eventually respiratory problems and death. On the other hand, botulinum neurotoxin is used in medicine and psychiatry. BoNT is involved in the management and control of many diseases such as depression and Parkinson's, dermatitis such as psoriasis, as well as in the beauty and elimination of facial skin wrinkles.

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Neuronal delivery of antibodies has therapeutic effects in animal models of botulism

Cited by 27 publications

References 47 publications

A Rabbit Model for the Evaluation of Drugs for Treating the Chronic Phase of Botulism

A Rabbit Model for the Evaluation of Drugs for Treating the Chronic Phase of Botulism

Probing the structure and function of the protease domain of botulinum neurotoxins using single-domain antibodies

Epidemiological aspects of poisoning Infectious-toxic bacteria of botulism on food poisoning in Iran; A review study

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