New strategies for severe ocular surface and corneal disease

Shu-I Yeh, MD, PhD;

New strategies for severe ocular surface and corneal disease

March 29, 2023

By Shu-I Yeh, MD, PhD

Publication

Article

Ophthalmology Times EuropeOphthalmology Times Europe April 2023

Volume 19

Issue 03

Regenerative technologies are providing an influx of options.

The cornea is a clear tissue at the front of the eye which 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. According to CDC statistics, the legally blind population in the United States increased from 3.4 to 4.2 million between 2003 and 2012 and is predicted to reach 8.96 million by 2050¹ with 5% of cases being caused by corneal opacification.²

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 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 the corneal integrity and lead to various levels of damage, scarring and blurred vision.

Shu-I Yeh, MD, PhD

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 (ie, inflammation) or extensive injury (ie, 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 Treatment for the resulting corneal damage remains a significant unmet medical need.

From eyedrops to surgery: 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 (OSR) or corneal transplant.^8,9 Rebuilding the corneal surface structure and re-epithelisation are complex processes. However, as our understanding of limbal stem cell biology progresses and novel technologies and therapeutic strategies are 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 anti-angiogenic, 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-epithelialisation. However, AMT is only effective if enough limbal stem cells remain. This means that procedures such as conjunctival limbal autograft, simple limbal epithelial transplantation and cultivated limbal epithelial transplantation may be required to replenish the limbal stem cells with the hope 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, whereas 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 the aforementioned options fail then 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 rate drops to about 50% after 10 years.¹⁰

Innovative treatments

Novel regenerative technologies are being developed, 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 patients with severe dry eye.¹¹ Several biotech companies are also developing stem cell and gene therapies that show potential. However, the price tag, performance consistency and need
for biological sources remain major barriers to the wider adoption of these techniques.

Instead of using stem cells directly, 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 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, one regenerative peptide was able to successfully restore the limbal layer and fully recover its corneal healing function.¹² When applied to human patients with dry eye, 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 so far are promising.

Importantly, the therapeutic price of this type of regenerative peptide is more affordable than alternatives such as PRP or stem cell therapies, 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 a single active pharmaceutical ingredient. Furthermore, there are future options to combine regenerative peptides with 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 for full relief from their conditions soon.