GHRH Receptor-Targeted Botulinum Neurotoxin Selectively Inhibits Pulsatile GH Secretion in Male Rats

Botulinum neurotoxin is a potent inhibitor of acetylcholine secretion and acts by cleaving members of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor family, which are critical to exocytotic vesicular secretion. However, the potential of botulinum neurotoxin for treating secretory disease is limited both by its neural selectivity and the necessity for direct injection into the relevant target tissue. To circumvent these limitations, a technology platform called targeted secretion inhibitors (TSIs) is being developed. TSIs are derived from botulinum neurotoxin but are retargeted to specific cell types to inhibit aberrant secretion. A TSI called qGHRH-LHN/D, with a GHRH receptor targeting domain and designed to specifically inhibit pituitary somatotroph GH release through cleavage of the N-ethylmaleimide-sensitive factor-attachment protein receptor protein, vesicle-associated membrane protein (VAMP), has recently been described. Here we show this TSI activates GHRH receptors in pri...