Novel approaches to treating severe ocular surface and corneal damage

Publication
Article
Digital EditionOphthalmology Times: July 2023
Volume 48
Issue 7

Severe ocular surface and corneal damage an unseen public health burden.

A close image of a female's brown eye. (Image Credit: AdobeStock/mik_cz)

(Image Credit: AdobeStock/mik_cz)

The cornea is a clear tissue at the very front of the eye that allows light transmission and serves as a protective barrier against mechanical, chemical, and pathogenic damage. A healthy cornea is vital for clear vision but if the cornea becomes damaged or diseased, it can significantly impact quality of life.

Corneal disease is a leading cause of blindness worldwide, with prevalence increasing dramatically with age and digital lifestyle. According to CDC statistics, the legally blind population in the US increased from 3.4 million to 4.2 million between 2003 and 2012 and is predicted to reach 8.96 million by 2050,1 with about 5% being caused by corneal opacification.2 Corneal disease is becoming a major public health burden and a worldwide health concern.

In its normal day-to-day life, the corneal surface epithelium, which has remarkable cell turnover and self-regenerating properties, shields the cornea from exposure to the external environment. The homeostasis of the corneal epithelium is supported by limbal stem cells that reside in the basal epithelium of the limbus, a transitional zone located between the cornea and conjunctiva. However, with a very finely tuned environment, the corneal epithelium is easily disrupted by factors such as abnormalities in the eyelids or tear film, damage to corneal nerves, physical or chemical ocular injuries, long-term contact lens wearing, or infections.3-5

Anything that hinders the cornea’s self-healing process may compromise corneal integrity and lead to various levels of damage, scarring, and blurred vision.

Even if corneal abrasions are extensive, the corneal epithelium can rapidly heal itself within 1 week in the presence of a healthy limbus. However, if the limbus experiences persistent challenges (eg, inflammation) or extensive injury (eg, chemical burns), then severe corneal damage may occur. In this scenario, early intervention with active treatments may help to salvage vision, but some cases are so severe that standard therapies are no longer effective, especially if the limbal stem cells are heavily injured or impaired. This injury is a major cause of visual impairment, with an estimated 1.5 million US patients suffering from visual impairment caused by ocular surface diseases.6 The resulting corneal damage remains a significant unmet medical need.

From eye drops to surgery: Current treatment options

Depending on the severity and extent of corneal surface damage, different clinical treatment options are available. For mild and moderate corneal epithelial erosions, antibiotics and/or anti-inflammatory eye drops can prevent or treat causal infections. This allows the natural repair mechanism of the limbal stem cells to start the wound healing process, avoiding further damage and controlling symptoms. A pain relief eye drop can also be used to provide patients with instant relief during the early stages of repair.7

For patients with severe corneal surface damage, medications alone are no longer helpful. In these cases, it may be necessary to undergo surgery for ocular surface reconstruction or corneal transplant.8-9 Rebuilding the corneal surface structure and re-epithelization are complex processes. However, as our understanding of limbal stem cell biology progresses and novel technologies and therapeutic strategies is developed, the range of procedures available to patients is rapidly advancing.

Amniotic membrane transplantation (AMT) can be applied in various indications of ocular surface and corneal damage because it contains several antiangiogenic, anti-inflammatory, epitheliotropic, and neurotrophic factors.

AMT may be used as a biological bandage over the diseased corneal surface with the aim of promoting corneal wound healing and re-epithelialization. Nevertheless, AMT is effective only if a sufficient number of limbal stem cells remain. This means procedures such as conjunctival limbal autograft, simple limbal epithelial transplantation, and cultivated limbal epithelial transplantation may be required to replenish the limbal stem cells in the hopes of restoring their natural repair mechanism.

These procedures have several limitations: Some require the extraction of a large piece of limbal tissue from the contralateral healthy eye, while others call for fresh donor limbal tissue or complex ex vivo/in vitro cell culture procedures with challenging quality control and economic burden. In addition, if donor limbal stem cells are allogenic, the patient may need lifelong immunosuppressive medications.

Finally, if all aforementioned options fail, patients may need a corneal transplant with either a cadaver cornea or, as a last resort, an artificial cornea.10 Even this may not provide a permanent solution: Although 90% of transplants remain intact after 5 years, this drops to just 50% after 10 years.10

Innovative novel treatments

New regenerative technologies are being developed all the time, providing a constant influx of new treatment options for patients. Autologous serum or platelet-rich plasma (PRP) eye drops containing several blood-derived growth factors have gained popularity in the treatment of ocular surface disease over recent years, especially among severe dry eye patients.11 Several biotech companies are also actively developing stem cell and gene therapies that show exciting potential. However, the price tag, performance consistency, and need for biological sources remain major barriers to the wider adoption of these techniques.

Recent advances have also uncovered a novel way to restore the limbus by using regenerative peptides that can stimulate limbal stem cells. Regenerative peptides offer a different approach from using the stem cells directly that can stimulate the remaining limbal stem cells to repair and regenerate at the site of damage while avoiding the uncertainties involved in the in vitro cell culture. Developing regenerative peptides offers an exciting opportunity to help patients with unmet needs in an affordable, accessible, and predictable way.

As demonstrated in animal models with over 70% limbus removal, 1 regenerative peptide was able to successfully restore the limbal layer and fully recover its corneal healing function.12 When applied to human dry eye patients, the peptide can speed up the healing process and relieve dry eye burning and stinging symptoms within 1 week.13 The regenerative peptide is still awaiting phase 3 trials for dry eye and phase 2 trials for neurotrophic keratitis (often accompanied by severe corneal ulceration or perforation), but the results thus far are promising.

Importantly, this type of regenerative peptide is significantly more affordable than alternatives such as PRP or stem cell therapies, largely because of the lower manufacturing cost per dose of synthetic peptides. In addition, this new type of corneal regenerative therapy is expected to have a high-performance consistency because it depends on only a single active pharmaceutical ingredient.

Furthermore, there are future options to combine regenerative peptides with current stem cell grafting methods to ensure limbal stem cell regeneration, improving the success rate of ocular surface and corneal damage treatments in restoring eyesight and preventing blindness.

In conclusion, regenerative peptides bring new hope to patients with severe corneal damage, offering the possibility of full relief from their conditions in the near future.

Shu-I Yeh, MD, PhD
E: shuiyeh@gmail.com
Yeh is an employee of Mackay Memorial Hospital in Taipei, Taiwan. She has no financial disclosures related to the content in this article.

References:
  1. Fast facts about vision loss. Centers for Disease Control and Prevention. Reviewed December 19, 2022. Accessed April 9, 2023. https://www.cdc.gov/visionhealth/basics/ced/fastfacts.htm
  2. Tidke SC, Tidake P. A review of corneal blindness: causes and management. Cureus. 2022;14(10):e30097. Doi:10.7759/cureus.30097
  3. Willmann D, Fu L, Melanson SW. Corneal injury. In: StatPearls. StatPearls Publishing; 2022.
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  7. Townsend WD, Sclafani L, Grohe RM, Casser L. Size, severity of injury, level of pain determine treatment for corneal abrasion. Primary Care Optometry News. December 1, 1999. Accessed April 2023. https://www.healio.com/news/optometry/20120225/size-severity-of-injury-level-of-pain-determine-treatment-for-corneal-abrasion
  8. Mobaraki M, Abbasi R, Omidian Vanchali S, Ghaffari M, Moztarzadeh F, Mozafari M. Corneal repair and regeneration: current concepts and future directions. Front Bioeng Biotechnol. 2019;7:135. doi:10.3389/fbioe.2019.00135
  9. Dong Y, Peng H, Lavker RM. Emerging therapeutic strategies for limbal stem cell deficiency. J Ophthalmol. 2018;2018:7894647. doi: 10.1155/2018/7894647
  10. Holland G, Pandit A, Sánchez-Abella L, et al. Artificial cornea: past, current, and future directions. Fron Med (Lausanne). 2021;8:770780.doi:10.3389/fmed.2021.770780
  11. Madan M. Using platelet-rich plasma eye drops in dry eye therapy. Eyes on Eyecare. July 28, 2021. Accessed April 10, 2023.https://eyesoneyecare.com/resources/using-platelet-rich-plasma-eye-drops-in-dry-eye-therapy/
  12. Yeh SI, Ho TC, Chen SL, et al. Pigment epithelial-derived factor peptide regenerated limbus severs as regeneration source for limbal regeneration in rabbit limbal deficiency. Invest Ophthalmol Vis Sci. 2016;57(6):2629-2636. doi:10.1167/iovs.15-17171
  13. Huang PY, Tsao YP, Tou, C, et al. Topical BRM421 ophthalmic solution improves signs and symptoms. Invest Opthalmol Vis Sci. 2021;62:1335.
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