title: Pre-Clinical Study of a Novel Recombinant Botulinum Neurotoxin Derivative Engineered for Improved Safety.
abstract: Cyto-012 is a recombinant derivative of Botulinum neurotoxin Type A (BoNT/A). It primarily differs from wild type (wt) BoNT/A1 in that it incorporates two amino acid substitutions in the catalytic domain of the light chain (LC) metalloprotease (E224 > A and Y366 > A), designed to provide a safer clinical profile. Cyto-012 is specifically internalized into rat cortical and hippocampal neurons, and cleaves Synaptosomal-Associated Protein 25 (SNAP-25), the substrate of wt BoNT/A, but exhibits slower cleavage kinetics and therefore requires a higher absolute dose to exhibit pharmacologic activity. The pharmacodynamics of Cyto-012 and wt BoNT/A have similar onset and duration of action using the Digital Abduction Assay (DAS). Intramuscular LD50 values for Cyto-012 and wt BoNT/A respectively, were 0.63 ug (95% CI = 0.61, 0.66) and 6.22 pg (95% CI = 5.42, 7.02). ED50 values for Cyto-012 and wt BoNT/A were respectively, 0.030 ug (95% CI = 0.026, 0.034) and 0.592 pg (95% CI = 0.488, 0.696). The safety margin (intramuscular LD50/ED50 ratio) for Cyto-012 was found to be improved 2-fold relative to wt BoNT/A (p < 0.001). The DAS response to Cyto-012 was diminished when a second injection was administered 32 days after the first. These data suggest that the safety margin of BoNT/A can be improved by modulating their activity towards SNAP-25.
authors.affiliation: CytoDel® LLC, New York, 10027, United States.|New York University School of Medicine, Department of Pharmacology and Molecular Biochemistry, New York, 10016, United States.|City College of New York, Department of Biology, New York, 10023, United States.
authors.forename: Edwin
authors.initials: E
authors.lastname: Vazquez-Cintron
authors.affiliation: CytoDel® LLC, New York, 10027, United States.|New York University School of Medicine, Department of Pharmacology and Molecular Biochemistry, New York, 10016, United States.
authors.forename: Luis
authors.initials: L
authors.lastname: Tenezaca
authors.affiliation: New York University School of Medicine, Department of Pharmacology and Molecular Biochemistry, New York, 10016, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Angeles
authors.affiliation: New York University School of Medicine, Department of Pharmacology and Molecular Biochemistry, New York, 10016, United States.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Syngkon
authors.affiliation: Harvard University, Office of Institutional Research, Cambridge, 02138, United States.
authors.forename: Victoria
authors.initials: V
authors.lastname: Liublinska
authors.affiliation: New York University School of Medicine, Department of Pharmacology and Molecular Biochemistry, New York, 10016, United States.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Ichtchenko
authors.affiliation: CytoDel® LLC, New York, 10027, United States.|New York University School of Medicine, Department of Pharmacology and Molecular Biochemistry, New York, 10016, United States.|Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, 10003, United States.
authors.forename: Philip
authors.initials: P
authors.lastname: Band
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000493:pharmacokinetics / Q000633:toxicity*; D002478:Cells, Cultured; D005260:Female; D007928:Lethal Dose 50; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009465:Neuromuscular Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D009465:Neuromuscular Agents; D011994:Recombinant Proteins; D019274:Botulinum Toxins, Type A