Ophthalmic Solution of Smart Supramolecular Peptides to Capture Semaphorin 4D against Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is the leading cause of vision loss in working age population. Intravitreal injection of anti‐VEGF antibody is widely used in clinical practice. However, about 27% of patients show poor response to anti‐VEGF therapy and about 50% of these patients continue to have macular thickening. Frequent intravitreal injections of antibody may increase the chance of endophthalmitis and cause visual loss or even blindness once happened. Therefore, there is a greatly urgent need for novel noninvasive target to treat DR clinically. Here, the formulation of a smart supramolecular peptide (SSP) eye drop for DR treatment that is effective via specifically identifying and capturing soluble semaphorin 4D (sSema4D), a strongly pro‐angiogenesis and exudates factor, is reported. The SSP nanostructures encapsulate sSema4D so that all biological effects mediated by three receptors of sSema4D are inhibited, thereby significantly alleviating pathological retinal angiogenesis and exudates in DR. Moreover, it is found that combination of SSPs eye drop and anti‐VEGF injection shows better therapeutic effect over anti‐VEGF treatment alone. Overall, SSP eye drop provide an alternative and effective method for noninvasive treatment for DR.

Recent advances in the treatment and delivery system of diabetic retinopathy

“…4D binding to the three receptors, achieving a significant reduction in pathologic retinal neovascularization and leakage. What's more, this study confirmed that in DR treatment, non-invasive SSP eye drops can achieve the same therapeutic effect as invasive antibody injections, when SSP eye drops combined with anti-VEGF can increase the current clinical therapeutic effect by 50% (154). Curcumin (CUR) and many other plant-derived polyphenolic compounds are known to act on multiple signaling pathways simultaneously; however, most of them have low bioavailability after oral administration, resulting in poor clinical efficacy.…”

“…4D binding to the three receptors, achieving a significant reduction in pathologic retinal neovascularization and leakage. What’s more, this study confirmed that in DR treatment, non-invasive SSP eye drops can achieve the same therapeutic effect as invasive antibody injections, when SSP eye drops combined with anti-VEGF can increase the current clinical therapeutic effect by 50% ( 154 ).…”

Sema4D Knockout Attenuates Choroidal Neovascularization by Inhibiting M2 Macrophage Polarization Via Regulation of the RhoA/ROCK Pathway

“…Furthermore, other studies have demonstrated that either genetic disruption of Sema4D/PlexinB1 or pharmacological inhibition of Sema4D significantly mitipathological retinal angiogenesis and vascular leakage in the oxygen-induced retinopathy model, as well as reduced pericyte loss in the streptozotocin-induced diabetes model. 29,41 Meanwhile, they also observed no significant difference in retinal vascular development between Sema4D-KO mice and their littermate WT mice. 29 Our current study revealed that Sema4D is highly expressed in macrophages within CNV lesions and plays a significant role in regulating pathological neovascularization and leakage.…”

“…Accumulating evidence has highlighted the importance of Sema4D and its downstream RhoA/ROCK pathway in the occurrence and progression of multiple neovascular diseases, including DR, 29 , 41 whereas their roles in neovascular AMD have not yet been elucidated. Herein, we reported that Sema4D mRNA and protein expression were significantly elevated over time in a laser-induced CNV model, especially in aged mice.…”

Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: from the perspective of cellular and molecular components

“…Sema4D can be proteolytic cleaved into its soluble form (sSema4D) and then shed from the cell surface. The level of sSema4D is significantly upregulated in the vitreous humor of patients with DR comparing to that in patients with macular hole, as well as upregulated in streptozotocin-induced mouse DR model [ 242 ]. The aqueous sSema4D, a strongly pro-angiogenesis and permeable factor, was reported to be positively correlated with the central subfield thickness in patients with DR [ 242 ].…”