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

• Published in: The Journal of clinical investigation Vol. 122; no. 9; pp. 3295 - 3306
• Main Authors: Somm, Emmanuel, Bonnet, Nicolas, Martinez, Alberto, Marks, Philip M H, Cadd, Verity A, Elliott, Mark, Toulotte, Audrey, Ferrari, Serge L, Rizzoli, René, Hüppi, Petra S, Harper, Elaine, Melmed, Shlomo, Jones, Richard, Aubert, Michel L
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2012
• Subjects: Acromegaly - drug therapy; Animals; Area Under Curve; Biomedical research; Body Weight - drug effects; Bones; Botulinum toxin; Botulinum Toxins - chemistry; Botulinum Toxins - genetics; Cell Line; Chemical bonds; Cyclic AMP - metabolism; Density; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Genetic regulation; Growth Hormone - blood; Growth Hormone - secretion; Growth Hormone-Releasing Hormone - chemistry; Growth Hormone-Releasing Hormone - genetics; Growth hormones; Growth Inhibitors - chemistry; Growth Inhibitors - pharmacology; Growth Plate - drug effects; Growth Plate - growth & development; Growth Plate - pathology; Health aspects; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - secretion; Ligands; Liver - metabolism; Male; Mortality; Organ Size - drug effects; Pituitary Gland - drug effects; Pituitary Gland - metabolism; Pituitary Gland - pathology; Pituitary hormones; Prolactin - metabolism; Protein Structure, Tertiary; Proteins; Proteolysis; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - pharmacology; Vesicle-Associated Membrane Protein 2 - chemistry; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI63232

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.