PIPELINE | CV-08
Peptide-Filled Capsules For The Treatment Of Severe Obesity
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.
We are currently investigating size-minimized cell-permeable SOCS3 peptide (CP-SP) without any complex manufacturing process. The goal of the project is to use advanced macromolecule transduction domain (aMTD) to deliver a competitive protein-based inhibitor to disrupt the binding of endogenous SOCS3 and ObR. We observed that CP-SP was efficiently delivered into cells and target tissue, by penetrating blood brain barrier (BBB). CP-SP is being developed to overcome leptin resistance, and to investigate whether leptin-induced anti-appetite signals can be maintained for the treatment of severe obesity. We proved that CP-SP has an anti-obesity effect in high-fat diet induced obesity (DIO) mouse model with 10.7 % body weight loss by daily application for 3 weeks.
We also confirmed that abdominal fat mass of CP-SP treated DIO mice is 8% less than that of DIO mice without CP-SP treatment. These findings suggest that the therapeutic applicability of CP-SP fused to aMTD as an anti-obesity agent to restore normal appetite.
We are currently developing CP-SP as a capsule formation collaborate with CROs and CMOs so that CP-SP can be applied with patient-friendly way. CV-08 project will be an effective therapeutic approach to patients who are suffering from severe obesity.
Figure 1. μCT shows fat volume decrease of CP-SP in diet-induced obesity mouse model (red-color area: abdominal fat).