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

Abstract

. 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.

Expert consensus document: A consensus on the medical treatment of acromegaly

“…30 Novel therapeutic approaches in early stages of clinical development include an antisense oligonucleotide of 20 bases that binds to the GH receptor mRNA and inhibits translation of the receptor protein, and a targeted secretion inhibitor, comprising a botulinum toxin-GH-releasing hormone (GHRH) chimera molecule that binds to cells expressing GHRH receptors, internalizes botulinum toxin and inhibits GH secretion. 73 Temozolomide, an alkylating agent that induces DNA damage thereby effecting tumour cell death, has been assessed for GH-aggressive pituitary tumours resistant to conventional therapy. 74,75 Further study results are required to assess the potential role of these agents in the medical therapy of acromegaly.…”

Botulinum neurotoxin type C protease induces apoptosis in differentiated human neuroblastoma cells

“…Further work is needed to investigate enzyme coupling and delivery strategies to achieve novel therapeutics for neuroblastomas and this may involve re-engineering of both the C protease and its translocation domain. Recently, an engineered version of botulinum neurotoxin type D was shown to be therapeutically relevant in the treatment of acromegaly opening new avenues for the use of engineered botulinum constructs in medicine [27]. …”

Botulinum neurotoxin: Progress in negating its neurotoxicity; and in extending its therapeutic utility via molecular engineering. MiniReview

“…These changes were accompanied by a fall in hepatic and plasma insulin-like growth factor 1 (IGF1) levels. Such a modified BoNT was viewed with the potential to treat acromegaly [Somm et al 2012]. …”