# Corneal Neovascularization: Pathogenesis, Current Insights and Future Strategies

## TL;DR

This paper reviews the causes and treatments for corneal neovascularization, a condition that causes vision loss and explores new therapies like gene-based and nanoparticle treatments.

## Contribution

The paper highlights novel therapeutic approaches such as gene-based treatments and advanced drug delivery systems for managing corneal neovascularization.

## Key findings

- Current treatments for corneal neovascularization include anti-inflammatory eye drops and anti-VEGF injections.
- Emerging therapies involve gene-based approaches and nanoparticles to improve drug delivery and effectiveness.
- Combination therapies targeting multiple pathways may offer better outcomes for patients with corneal neovascularization.

## Abstract

Corneal clarity is maintained by its avascular and immune-privileged status under normal circumstances. Secondary to pathological insult, new immature blood vessels may invade the cornea resulting in profound visual loss and permanent corneal damage. This review article summarises current knowledge on pathological mechanisms by which the neovascularization occurs and its management. This review explores the strengths and limitations of existing treatments, including anti-inflammatory eye drops, injections of agents blocking signals promoting vessel growth, laser treatments and fine-needle diathermy procedures. Novel cutting-edge approaches are highlighted, which involve advanced drug-delivery methods, gene-based therapeutics, and treatments using stem cells or nanoparticles. As corneal neovascularization is a significant cause of preventable vision loss worldwide, novel treatments may prevent disease progression and preserve good visual outcomes in patients. Emphasis is placed on future treatments requiring a combination approach to prove efficient control and cessation of neovascularization.

The cornea is an avascular, immune-privileged tissue critical to maintaining transparency, optimal light refraction, and protection from microbial and immunogenic insults. Corneal neovascularization (CoNV) is a pathological sequela of multiple anterior segment diseases and presents a major cause for reduced visual acuity and overall quality of life. Various aetiologies, including infection (e.g., herpes simplex), inflammation (e.g., infective keratitis), hypoxia (e.g., contact lens overuse), degeneration (e.g., chemical burns), and trauma, disrupt the homeostatic avascular microenvironment, triggering an overactive compensatory response. This response is governed by a complex interplay of pro- and anti-angiogenic factors. This review investigates the potential for these mediators to serve as therapeutic targets. Current therapeutic strategies for CoNV encompass topical corticosteroids, anti-VEGF injections, fine-needle diathermy, and laser modalities including argon, photodynamic therapy and Nd:YAG. Emerging therapies involve steroid-sparing immunosuppressants (including cyclosporine and rapamycin), anti-fibrotic agents and advanced drug delivery systems, including ocular nanosystems and viral vectors, to enhance drug bioavailability. Adjunctive therapy to attenuate the protective corneal epithelium prior to target neovascular plexi are further explored. Gene-based approaches, such as Aganirsen (antisense oligonucleotides) and CRISPR/Cas9-mediated VEGF-A editing, have shown promise in preclinical studies for CoNV regression and remission. Given the multifactorial pathophysiology of CoNV, combination therapies targeting multiple molecular pathways may offer improved visual outcomes. Case studies of CoNV highlight the need for multifaceted approaches tailored to patient demographics and underlying ocular diseases. Future research and clinical trials are essential to elucidate optimal therapeutic strategies and explore combination therapies to ensure better management, improved treatment outcomes, and long-term remission of this visually disabling condition.