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

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

Science translational medicine (2021-01-08)
Patrick M McNutt, Edwin J Vazquez-Cintron, Luis Tenezaca, Celinia A Ondeck, Kyle E Kelly, Mark Mangkhalakhili, James B Machamer, Christopher A Angeles, Elliot J Glotfelty, Jaclyn Cika, Cesar H Benjumea, Justin T Whitfield, Philip A Band, Charles B Shoemaker, Konstantin Ichtchenko
ABSTRACT

Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that atoxic BoNT derivatives can be harnessed to deliver therapeutic protein moieties to the neuronal cytoplasm where they bind and neutralize intracellular targets in experimental models. The generalizability of this platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
d-Desthiobiotin, ≥98% (TLC)
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
Sigma-Aldrich
Polyethylenimine, branched, average Mw ~25,000 by LS, average Mn ~10,000 by GPC, branched
Sigma-Aldrich
L-Glutathione reduced, ≥98.0%
Sigma-Aldrich
Poly-D-lysine hydrobromide, mol wt 70,000-150,000, lyophilized powder, γ-irradiated, BioReagent, suitable for cell culture
Sigma-Aldrich
Prionex® Highly purified Type A, aqueous solution
Sigma-Aldrich
Gelatin solution, Type B, 2% in H2O, tissue culture grade, BioReagent, suitable for cell culture
Sigma-Aldrich
Anti-LAMP-1 (CD107a) Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
L-Glutathione oxidized, ≥98% (HPLC)