PIPELINE | CV-08
The abnormal control of leptin, an adipocyte-secreted hormone controlling appetite, chronically causes morbid obesity as it accumulates excessive body fat.
On binding to leptin receptor (ObR) expressed in hypothalamic neurons, leptin evokes JAK/STAT signaling, and induces the expression of suppressor of cytokine signaling 3 (SOCS3) as a negative feedback regulator to maintain the homeostatic balance between food intake and fat accumulation. However, excessive leptin in obesity increases level of endogenous SOCS3 which promotes “leptin resistance” and disables the appetite-control by leptin. Due to this phenomenon, leptin-based therapeutic approach failed to effectively cure severely-obese patients, though it had previously been considered as an attractive anti-obesity strategy.
The goal of the project was to use advanced macromolecule transduction domain (aMTD) to deliver a competitive protein-based inhibitor to disrupt the binding of SOCS3 and ObR. Cell-permeable (CP) truncated SOCS3 recombinant protein (CP-ΔSOCS3) has been developed to overcome leptin resistance, and to investigate whether leptin-induced anti-appetite signals can be maintained for the treatment of severe obesity.
We observed that CP-ΔSOCS3 was efficiently delivered into cells and tissues including hypothalamus by penetrating blood brain barrier (BBB), and directly interacted with ObR and enhanced leptin signaling in vitro and in vivo.
Diet-induced obese (DIO) mice treated with CP-ΔSOCS3 shows 26% of body weight decreased under the regular-fat diet (RFD) condition and 12% of body weight decreased under the high-fat diet (HFD) condition through regulating the expression of appetite regulatory marker and energy expenditure marker. In addition, CP-ΔSOCS3 improved fatty liver and reduced total cholesterol level of obese mouse. Furthermore, CP-ΔSOCS3 decreased the blood glucose level in DIO mice indicating that it may have therapeutic effect on type II diabetes. Therefore, we have successfully demonstrated the therapeutic applicability of CP-ΔSOCS3 fused to aMTD as a mechanism-specific anti-obesity agent to restore normal appetite as well as type II diabetes.
Currently, CP-ΔSOCS3 is in preclinical studies by performing process development, manufacturing, encapsulation and analytical method development at global CROs and CMOs.