Advances in targeting the extracellular matrix for glaucoma therapy: current updates

ABSTRACTIntroduction Elevated intraocular pressure (IOP) is a well-recognized risk factor for development of primary open angle glaucoma (POAG), a leading cause of irreversible blindness. Ocular hypertension is associated with excessive extracellular matrix (ECM) deposition in trabecular meshwork (TM) resulting in increased aqueous outflow resistance and elevated IOP. Hence, therapeutic options targeting ECM remodeling in TM to lower IOP in glaucomatous eyes are of considerable importance.Areas covered This paper discusses the complex process of ECM regulation in TM and explores promising therapeutic targets. The role of Transforming Growth Factor-β as a central player in ECM deposition in TM is discussed. We elaborate the key regulatory processes involved in its activation, release, signaling and crosstalk with other signaling pathways including Rho GTPase, Wnt, integrin, cytokines, and renin-angiotensin-aldosterone. Further we summarize the therapeutic agents that have been explored to target ECM dysregulation in TM.Expert opinion Targeting molecular pathways to reduce ECM deposition and/or enhance its degradation are of considerable significance for IOP lowering. Challenges lie in pinpointing specific targets and designing drug delivery systems to precisely interact with pathologically active/inactive signaling. Recent advances in monoclonal antibodies, fusion molecules, and vectored nanotechnology offer potential solutions.KEYWORDS: Glaucomaextracellular matrixtherapeutic targetsTransforming growth factor-betaDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). 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Article highlights:Dysregulation of ECM turnover in the TM is a primary pathology in glaucoma, leading to increased outflow resistance and elevated IOP.TGF-β, especially its -β2 isoform, plays a central role in ECM-related protein expression and cytoskeleton alterations in TM.Targeting the release of active TGF-β, precise modulation of TGF-β-regulated genes, and crosstalk offer potential avenues for intervention to restore ECM homeostasis.Enhancing ECM breakdown through proteolytic activity within the ECM is also a promising strategy to reduce aqueous outflow resistance in glaucoma.Precision delivery of therapeutic agents to the TM through vectored nanotechnology is a promising strategy for effectively targeting specific pathways and minimizing risks in glaucoma treatment.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Figure 1: Diagrammatic representation of the dysregulation of ECM homeostasis causing increased aqueous outflow resistance and a central role of transforming growth factor (TGF)-β, particularly its β2 isoform. The consequences of TGF-β2 signaling and its crosstalk with other signaling pathways are depicted. Lines with arrowhead indicate a positive regulation and lines with blunt head indicate a negative regulation. ADMTS: A disintegrin and metalloproteinase with thrombospondin motifs; BAMBI: BMP and activin membrane-bound inhibitor; BMP: Bone morphogenic protein; ECM: Extracellular matrix; IL: Interleukin; MMP: Matrix metalloproteinase; PTEN: Phosphatase and tensin homolog; TIMP: Tissue inhibitor of metalloproteinase TNF: Tumor necrosis factor.Display full sizeFigure 2: Diagrammatic representation of the role of fibrinolytic pathway in ECM proteolysis in trabecular meshwork. Interaction of various signaling pathways influencing the activity of ECM proteolysis in trabecular meshwork is depicted. Lines with arrowhead indicate a positive regulation and lines with blunt head indicate a negative regulation. BMP: Bone morphogenic protein; ECM: Extracellular matrix; PAI: Plasminogen activator inhibitor; TGF: Transforming growth factor; t-PA: Tissue plasminogen activator; u-PA: Urokinase-type plasminogen activatorDisplay full sizeACE: Angiotensin converting enzyme; Akt: Protein kinase B; A1R: Angiotensin II type 1 receptor; ATR kinase: Ataxia telangiectasia and Rad3-related kinase; CTGF: Connective tissue growth factor; ERK: Extracellular regulated kinase; LAP: Latency associated protein; miR: MicroRNA; MLC: Myosin light chain; PTEM: Phosphatase and tensin homolog; ROCH: Rho associated kinase; shRNA: short/small hairpin RNA; siRNA: Small interfering RNA; TGF-β: Transforming growth factor; TGF-β1R: Transforming growth factor receptor type 1; TLR: Toll-like receptor; TSP: Thrombospondin; 3′-UTR: Three prime untranslated regionAdditional informationFundingAuthors acknowledge the financial support by Ministry of Higher education, Government of Malaysia, under the grant no. FRGS/1/2020/SKK0/IMU/01/1 and FRGS/1/2023/SKK15/IMU/01/1.