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

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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 9 Pg. 3295-306 (Sep 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 22850878 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Growth Inhibitors
• Recombinant Fusion Proteins
• SXN101742 protein
• Vesicle-Associated Membrane Protein 2
• insulin-like growth factor-1, rat
• Insulin-Like Growth Factor I
• Prolactin
• Growth Hormone
• Growth Hormone-Releasing Hormone
• Cyclic AMP
• Botulinum Toxins

Topics

• Acromegaly (drug therapy)
• Animals
• Area Under Curve
• Body Weight (drug effects)
• Botulinum Toxins (chemistry, genetics)
• Cell Line
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Growth Hormone (blood, metabolism)
• Growth Hormone-Releasing Hormone (chemistry, genetics)
• Growth Inhibitors (chemistry, pharmacology)
• Growth Plate (drug effects, growth & development, pathology)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Liver (metabolism)
• Male
• Organ Size (drug effects)
• Pituitary Gland (drug effects, metabolism, pathology)
• Prolactin (metabolism)
• Protein Structure, Tertiary
• Proteolysis
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins (chemistry, pharmacology)
• Vesicle-Associated Membrane Protein 2 (chemistry)