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A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis
Emmanuel Somm, … , Richard Jones, Michel L. Aubert
Emmanuel Somm, … , Richard Jones, Michel L. Aubert
Published August 1, 2012
Citation Information: J Clin Invest. 2012;122(9):3295-3306. https://doi.org/10.1172/JCI63232.
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Research Article Endocrinology Article has an altmetric score of 19

A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis

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Abstract

Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2–amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.

Authors

Emmanuel Somm, Nicolas Bonnet, Alberto Martinez, Philip M.H. Marks, Verity A. Cadd, Mark Elliott, Audrey Toulotte, Serge L. Ferrari, René Rizzoli, Petra S. Hüppi, Elaine Harper, Shlomo Melmed, Richard Jones, Michel L. Aubert

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Figure 5

SXN101742-induced GH inhibition dose dependently decreases IGF1 levels and inhibits somatic growth in juvenile rats (experiment no. 2).

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SXN101742-induced GH inhibition dose dependently decreases IGF1 levels a...
(A) Relative gene expression for Igf1 in liver. *P < 0.001 versus control group; #P < 0.001 versus 0.1 mg/kg group; †P < 0.001 versus 0.3 mg/kg group. (B) IGF1 protein content in liver (ng/mg protein). *P < 0.001 versus control group; #P < 0.01 versus 0.1 mg/kg group. (C) Time course of plasma IGF1 levels (ng/ml). *P < 0.05 versus control group; #P < 0.05 versus 0.1 mg/kg group; †P < 0.05 versus 0.3 mg/kg group. Inset panel represents AUC, same significance as in the main panel. (D) BW curves (g). *P < 0.05 versus control group; #P < 0.05 versus 0.1 mg/kg group. (E) Food intake (g). *P < 0.05 versus control group; #P < 0.05 versus 0.1 mg/kg group. (F) Body length (cm). *P < 0.001 versus control group. For all panels, 45-day-old male rats received either a single i.v. injection of SXN101742 at the dose of 0.1, 0.3, or 1 mg/kg or vehicle and were studied over a 10-day period. Results are expressed as mean ± SEM. n = 8–10 animals per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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