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?

SUBMITTER: Vazquez-Cintron E 

PROVIDER: S-EPMC4971498 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature