Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

Abstract

Retinal neovascularization (NV) due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN) may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs) in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.

Periostin and tenascin-C interaction promotes angiogenesis in ischemic proliferative retinopathy

“…IL-13 is an important type 2 T helper (Th2) cytokine controlling biological functions in tissue remodeling such as angiogenesis and fibrosis [34][35][36][37] . We previously found IL-13 up-regulation in the vitreous humors of PDR patients and OIR mice retinas, which suggests that ischemic injury induces IL-13 expression and secretion in the retina 19,31 . Meanwhile, after central nervous system (CNS) injury by stroke, a shift towards Th2 response and downregulation of Th1 response play a role in tissue remodeling during CNS wound healing response 38 .…”

“…Our group subsequently demonstrated that PN and TNC were highly up-regulated in the vitreous humor of patients with PDR and proliferative vitreoretinopathy, and promoted both retinal angiogenesis and fibrosis in the pathogenesis of vitreoretinal diseases [17][18][19][20] . Accumulated evidence suggest that ECM components including PN, TNC and fibronectin (FN) that is a well-characterized molecule, promotes physiological and pathological retinal angiogenesis [21][22][23][24][25][26] .…”

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models

“…We found that BLT1 + cells infiltrated into the periphery of the macular drusen, a common early sign of AMD, and choroidal capillaries in the RPE-choroid of diabetic human eyes but not in nondiabetic human eyes. Recent studies show that infiltrated macrophages exhibit M2-phenotype, which accelerate neovascularization to promote tissue repair in the injured retina of retinopathy (38,79,89,90). Hence, the BLT1 may be a promising therapeutic target for CNV of several diseases, including wet AMD.…”

Paxillin promotes the migration and angiogenesis of HUVECs and affects angiogenesis in the mouse cornea

“…This gap increases bleeding and causes hyperplasia and pathological changes, which leads to irreversible damage to the structure and function of the eye, ultimately resulting in a serious decline in vision and potentially blindness. Keratitis is a common eye disorder that often leads to the formation of new blood vessels ( 5 , 6 ). Paxillin (PXN) is a focal adhesion protein, and is comprised of an LD motif (containing the consensus peptide sequence LDXLLXXL), a conserved cysteine-rich domain comprising of ~60 amino acids with seven conserved cysteine residues and a histidine residue (LIM domain), Src homology 2 (SH2) domain and Src homology 3 (SH3) domains ( 7 ).…”