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

ABSTRACT

Introduction

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 cross talk 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:

• Glaucoma
• extracellular matrix
• therapeutic targets
• transforming growth factor-beta
• Trabecular meshwork

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 cross talk offers 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 interest

The 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 disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Authors 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.