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

Martinez, Alberto
Marks, Philip M H
Cadd, Verity A
Elliott, Mark
Toulotte, Audrey
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Published in The Journal of clinical investigation. 2012, vol. 122, no. 9, p. 3295-3306
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.
Keywords Acromegaly/drug therapyAnimalsArea Under CurveBody Weight/drug effectsBotulinum Toxins/chemistry/geneticsCell LineCyclic AMP/metabolismDose-Response Relationship, DrugDown-Regulation/drug effectsGrowth Hormone/blood/secretionGrowth Hormone-Releasing Hormone/chemistry/geneticsGrowth Inhibitors/chemistry/pharmacologyGrowth Plate/drug effects/growth & development/pathologyInsulin-Like Growth Factor I/genetics/metabolism/secretionLiver/metabolismMaleOrgan Size/drug effectsPituitary Gland/drug effects/metabolism/pathologyProlactin/metabolismProtein Structure, TertiaryProteolysisRatsRats, Sprague-DawleyRecombinant Fusion Proteins/chemistry/pharmacologyVesicle-Associated Membrane Protein 2/chemistry
PMID: 22850878
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Research groups Génétique des Ostéoporoses (544)
L'imagerie cérébrale (184)
Nutrition et os (66)
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SOMM, Emmanuel et al. A botulinum toxin-derived targeted secretion inhibitor downregulates the GH/IGF1 axis. In: The Journal of clinical investigation, 2012, vol. 122, n° 9, p. 3295-3306. doi: 10.1172/JCI63232 https://archive-ouverte.unige.ch/unige:28593

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Deposited on : 2013-06-17

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