Tanzeel Huma,Xintian Hu,Yuanye Ma,Andrew Willden,Joshua Rizak,Muhammad Shahab,Zhengbo Wang
Embryonic stem cells (ESCs) have enormous potential as novel cell-based therapies, but their effectiveness depends on stem cell differentiation and specific signaling regulators, which remain poorly understood. In this study, a kisspeptin peptide (KP-10) was used at different dosages to determine whether rhesus macaque-derived tau GFP-Lyon ES cells underwent kisspeptin-specific neuronal differentiation. It was found that KP-10 exhibited an anti-proliferative effect on the cells and led to morphological changes and cellular differentiation consistent with neuronal stem cell (NSC) development. The cells differentiated into Gonadotrophin Releasing Hormone (GnRH) neuronal-like cell types in response to the KP-10 treatment. There has been a previously observed connection between kisspeptin signaling, GnRH neurons and their dysfunction found in congenital disorders like idiopathic hypogonadotropic hypogonadism (IHH). Although therapeutics are a still a far-off goal, the formation and development of GnRH-positive neuronal-like cells following the application of KP-10 to Lyon NSC cells opens the door for future NSC-based therapies to treat specific reproductive disorders.
Uncontrolled activation of complement and upregulation of vascular endothelial growth factor (VEGF) play fundamental roles in age-related macular degeneration (AMD). However, most drugs used to treat AMD focus on a single target, and the percentage of effectively treated patients in clinical practice needs to be improved. Therefore, novel AMD treatment approaches are needed. IBI302 is a novel bispecific decoy receptor fusion protein designed with both a VEGF inhibition domain and a complement cascade inhibition domain, which are connected by the Fc region of human immunoglobulin . In this study, we systematically evaluated the binding affinity between IBI302 and VEGF isoforms and complement proteins by using surface plasmon resonance (SPR) technology. Anti-VEGF blockers (aflibercept and bevacizumab) and complement receptor 1 were used as references. The SPR assay results indicated that IBI302 could bind different VEGF isoforms and complement proteins with high affinity. The biological activity of IBI302 was also studied. IBI302 showed an inhibitory effect on human primary umbilical vein endothelial cell proliferation and the activation of complement pathways in vitro. Finally, the pharmacokinetic (PK) properties of IBI302 were evaluated in rhesus monkeys . The PK results showed that after a 0.5 mg/eye intravitreal dosage, IBI302 became rapidly distributed from the vitreous humor into targeted tissues and remained active over 504 h. Overall, the favorable anti-angiogenic and anti-complement effects of IBI302 along with the good PK profiles in rhesus monkeys support the selection and development of IBI302 as a promising candidate for AMD treatment.
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