Author: Vignaud, Alban ; Beard, Matthew ; Rocher, Marie‐Noelle ; Kalinichev, Mikhail ; Favre‐Guilmard, Christine ; Wagner, Stéphanie ; Rudkin, Brian B. ; Lezmi, Stephane ; Martin, Vincent ; Bindler, Julien ; Cornet, Sylvie ; Andriambeloson, Emile ; Marty, Rudy ; Périer, Cindy

AbstractClinically used botulinum neurotoxins (BoNTs) are natural products of Clostridium botulinum. A novel, recombinant BoNT type A1 (rBoNT/A1; IPN10260) has been synthesized using the native amino acid sequence expressed in Escherichia coli and has previously been characterized in vitro and ex vivo. Here, we aimed to characterize rBoNT/A1 in vivo and evaluate its effects on skeletal muscle. The properties of rBoNT/A1 following single, intramuscular administration were evaluated in the mouse and rat digit abduction score (DAS) assays and compared with those of natural BoNT/A1 (nBoNT/A1). rBoNT/A1‐injected tibialis anterior was assessed in the in situ muscle force test in rats. rBoNT/A1‐injected gastrocnemius lateralis (GL) muscle was assessed in the compound muscle action potential (CMAP) test in rats. The rBoNT/A1‐injected GL muscle was evaluated for muscle weight, volume, myofiber composition and immunohistochemical detection of cleaved SNAP25 (c‐SNAP25). Results showed that rBoNT/A1 and nBoNT/A1 were equipotent and had similar onset and duration of action in both mouse and rat DAS assays. rBoNT/A1 caused a dose‐dependent inhibition of muscle force and a rapid long‐lasting reduction in CMAP amplitude that lasted for at least 30 days. Dose‐dependent reductions in GL weight and volume and increases in myofiber atrophy were accompanied by immunohistochemical detection of c‐SNAP25. Overall, rBoNT/A1 and nBoNT/A1 exhibited similar properties following intramuscular administration. rBoNT/A1 inhibited motoneurons neurotransmitter release, which was robust, long‐lasting, and accompanied by cleavage of SNAP25. rBoNT/A1 is a useful tool molecule for comparison with current natural and future modified recombinant neurotoxins products.

01 Sep 2019·ToxiconQ3 · MEDICINE

Comparative functional analysis of mice after local injection with botulinum neurotoxin A1, A2, A6, and B1 by catwalk analysis

Q3 · MEDICINE

Article

Author: Pellett, Sabine ; Johnson, Eric A ; Inzalaco, Heather N'te ; Moritz, Molly S ; Tepp, William H

Botulinum neurotoxins (BoNTs) are potent neurotoxins and are the causative agent of botulism, as well as valuable pharmaceuticals. BoNTs are divided into seven serotypes that comprise over 40 reported subtypes. BoNT/A1 and BoNT/B1 are currently the only subtypes approved for pharmaceutical use in the USA. While several other BoNT subtypes including BoNT/A2 and/A6 have been proposed as promising pharmaceuticals, detailed characterization using in vivo assays are essential to determine their pharmaceutical characteristics compared to the currently used BoNT/A1 and/B1. Several methods for studying BoNTs in mice are being used, but no objective and quantitative assay for assessment of functional outcomes after injection has been described. Here we describe the use of CatWalk XT as a new analytical tool for the objective and quantitative analysis of the paralytic effect after local intramuscular injection of BoNT subtypes A1, A2, A6, and B1. Catwalk is a sophisticated gait and locomotion analysis system that quantitatively analyzes a rodent's paw print dimensions and footfall patterns while traversing a glass plate during unforced walk. Significant changes were observed in several gait parameters in mice after local intramuscular injection of all tested BoNT subtypes, however, no changes were observed in mice injected intraperitoneally with the same BoNTs. While a clear difference in time to peak paralysis was observed between BoNT/A1 and/B1, injection of all four toxins resulted in a deficit in the injected limb with the other limbs functionally compensating and with no qualitative differences between the four BoNT subtypes. The presented data demonstrate the utility of CatWalk as a tool for functional outcomes after local BoNT injection through its ability to collect large amounts of quantitative data and objectively analyze sensitive changes in static and dynamic gait parameters.

01 Jun 2018·ToxiconQ3 · MEDICINE

Substrate cleavage and duration of action of botulinum neurotoxin type FA (“H, HA”)

Q3 · MEDICINE

Article

Author: Johnson, Eric A ; Lin, Guangyun ; Pellett, Sabine ; Tepp, William H

Botulinum neurotoxin (BoNT) type FA is the only known naturally occurring chimeric BoNT of domains of BoNT/A and BoNT/F. BoNT/FA consists of an F5-like light chain (LC), a unique heavy chain (HC) translocation domain, and a HC receptor binding domain similar to BoNT/A1. Previous analyses of purified BoNT/FA have indicated a 5-10-fold greater potency in cultured human or rat neurons as compared to BoNT/A1 and a 400-500-fold greater potency compared to BoNT/B1. However, in vivo potency in mice was about 5-fold lower than BoNT/A1 or/B1. In this report, species specificity was examined by cell-based assays using primary neurons from mice and examining VAMP1 and 2 cleavage. The data indicated similar potency of BoNT/FA in primary mouse spinal cord neurons as previously observed in primary rat and human induced pluripotent stem cell (hiPSC) derived neuronal cell models, and equal enzymatic cleavage of mouse VAMP1 and 2 isoforms. Since the duration of action of BoNTs is due to continuous enzymatic activity of the LC in the neuronal cytosol, BoNT/FA was expected to have a short duration of action due to its F-type LC. In this report the duration of action of BoNT/FA was compared to that of BoNT/F1,/F5, and/B1 in both hiPSC derived neurons and in the in vivo mouse model. The data indicate a duration of action of BoNT/FA similar to BoNT/B1, while BoNT/F5 had a short duration of action similar to BoNT/F1.

100 Deals associated with rBoNT/B1 (Ipsen)

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Preclinical	GB	Ipsen Ltd.	-
Nervous System Diseases	Preclinical	US	The Children's Hospital Corp.	-
Nervous System Diseases	Preclinical	SE	University of Stockholm	-

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