Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target

Abstract

Early PVR is characterized by activation of T cells and mTOR signaling, whereas advanced PVR is characterized by a chronic monocyte response. PVR might be treated by rational repositioning of existing drugs that target mTOR and IL-6. Our analysis demonstrates that successful therapeutic intervention will be highly dependent on the specific therapeutic target and the stage of PVR. This study provides insights into cytokines that will serve as biomarkers and therapeutic targets. These biomarkers will help design clinical trials that intervene at appropriate times.

Quantitative proteomic analyses in blood: A window to human health and disease

“…They found differential protein profiles in early versus advanced PVR as well as specific targets, mTOR and IL‐6, using hierarchical clustering and pathway analysis of array data. Their results suggest that repositioning of existing drugs that target mTOR and IL‐6 and therapeutic intervention dependent on the stage of PVR would be a future option . Additionally, Velez et al.…”

“…Their results suggest that repositioning of existing drugs that target mTOR and IL-6 and therapeutic intervention dependent on the stage of PVR would be a future option. 128 Additionally, Velez et al used an Ab array to profile neovascular inflammatory vitreoretinopathy patients and identified potential drug targets and implicated molecular pathways to target with repositioned drugs as well as preventing delivery of ineffective drugs. 129 Not only does proteomic approaches provide insight into potential diseases existing drugs could be applied to but also into identifying which patients with a particular disease could benefit from a targeted therapy.…”

Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development

“…89 An early response to retinal detachment is the infiltration into the subretinal space of IL-1β-secreting macrophages which may contribute to photoreceptor death through the (nucleotide-binding oligomerization domain) NOD-like receptor family and pyrin-domaincontaining-3 protein inflammasome, 90 as well as stimulating RPE cells to upregulate inflammatory cytokines, including IL-6. 91 IL-1α and IL-1β are present in subretinal and vitreal fluid in cases of RRD and established PVR and are variably reported to be raised in PVR, 38,80,86 whereas other studies suggest that elevated IL-1α, but not IL-1β levels are associated with subsequent PVR risk. 9,92 Generic inflammatory cytokines are likely to be present in all eyes with retinal detachment irrespective of whether they subsequently develop PVR, and in the report suggesting IL-1α associated with subsequent PVR risk, there was extensive overlap between levels in patients who did and did not subsequently develop PVR, 9 suggesting limited utility as a biomarker.…”

“…[78][79][80][81][82][83] IL-6 can also stimulate corneal epithelial cells and stromal fibroblasts (and macrophages) to produce profibrotic VEGF. 78 Like most inflammatory cytokines, IL-6 is present in subretinal fluid in high titers during retinal detachment and RRD repair, 84,85 and their presence is correlated with the subsequent, development of postoperative PVR, 9 as well as being elevated in the vitreous of patients with early PVR, 38,86 and correlating with PVR severity when found in sub silicone-oil fluid, 87 but, because subretinal and vitreous IL-6 levels significantly overlap between patients with uncomplicated retinal detachment and severe or future PVR, they have limited biomarker potential.…”

Personalized Proteomics for Precision Health: Identifying Biomarkers of Vitreoretinal Disease

“…Its treatment often requires delicate and complex surgery to remove fibrotic membranes, often with poor visual outcomes. 86 , 87 These patients face numerous clinical risk factors, such as prior PVR, longer lasting RD, vitreous or choroidal hemorrhage, and poorer initial visual acuity. 86 Despite this, identification of clinical risk factors does little to improve PVR therapy.…”