A New Era in Treating Corneal Disease

The treatment of corneal diseases is undergoing a paradigm shift, which will overcome many of the shortcomings of current approaches to dealing with corneal dystrophies and other potentially blinding conditions, said Professor Jorge L Alió in his Binkhorst Medal Lecture at the 2023 ESCRS Congress in Vienna.

“We are at the forefront of an exciting revolution in the treatment of corneal blindness, moving from the old paradigm of cornea tissue substitution to one where cornea tissue regeneration becomes the new standard,” Prof Alió said.

The need for new treatments is pressing, he stressed, noting that corneal blindness is the second most common cause of blindness worldwide, with treatment limited by the number of donors for corneal transplants.

“The shortage of corneas results in over 40,000 visually impaired people waiting for corneal transplants every year in Europe alone, with 10 million untreated corneal blindness patients globally and 1.5 million new cases of corneal blindness annually,” he said.

This number is rising due to the ageing population and corneal graft failure, which often occurs due to rejection, becoming even more likely with each successive graft and new indication.

New solutions needed

“There is a need for new solutions to avoid tissue substitution, preferably immunologically neutral ones, independent from human donor tissue, with unlimited accessibility that will probably be more cost effective than corneal grafts in the long term,” he said.

Advanced stem cell therapies may be the game-changer everyone has been waiting for, added Prof Alió, who outlined some of the latest research in regenerative techniques for a wide range of corneal diseases.

Adipose-derived adult mesenchymal stem cells (ADASCs), for instance, have been shown to provide a viable cell source for stromal regeneration and repopulation in diseased corneas. ADASCs are typically isolated from adipose (fat) tissue obtained from the patient’s body, which reduces the risk of rejection or immune-related complications.

ADASCs can be induced to differentiate into epithelial cells or stromal cells in the laboratory and can help repair the corneal epithelium, stroma, or endothelium, depending on the specific corneal injury or disease.

These cells have demonstrated anti-inflammatory and immunomodulatory properties, which can be beneficial for reducing inflammation and immune responses in the damaged cornea. They may also stimulate endogenous repair mechanisms in the cornea by releasing growth factors and cytokines that promote tissue healing.

Mesenchymal stem cells (MSCs) are suitable extraocular stem cells for corneal regenerative therapy. “They can differentiate into other cell types; they have anti-fibrotic, anti-apoptotic, and anti-inflammatory capacities; and they are non-immunogenic, so they do not require immunosuppressive therapy,” Prof Alió said.

Stem cell deficiency

MSCs have shown promise for the treatment of ocular surface diseases such as dry eye, corneal burns, ulcers, and limbal stem cell deficiency (LSCD).

Prof Alió highlighted the pioneering work of Dr Margarita Calonge, who reported the first proof-of-concept clinical trial using MSCs for treating corneal epithelial stem cell deficiency in 22 patients.

“MSCs have a present and future critical role in the management of corneal epithelial failure due to limbal stem cell deficiency. Severe forms of dry eye disease have already been improved with MSC therapy in open-label clinical trials, with randomised controlled clinical trials to follow,” he said. “Cell-free therapy such as PRP—especially with MSC-extracellular vesicles (such as exosomes)—could be a future better option than MSCs, provided the many existing challenges can be solved.”

As well as epithelial repair, MSCs can be differentiated into corneal stromal cells in vitro and then transplanted into the corneal stroma to promote tissue regeneration. The cells can also be incorporated into tissue-engineered constructs or biodegradable scaffolds for corneal transplantation in thin corneas or cases where injection alone is insufficient to promote corneal regeneration.

The technique using ADASCs implanted into corneal stroma has already been successfully tested in the first human phase 1 and 2 trials in five patients with advanced keratoconus.

“The safety of the procedure has been demonstrated with local production of collagen by ADASCs in situ confirmed and recovery of the transparency of the implanted laminas confirmed,” he said. “The cases are stable after three years, opening the door for further clinical studies of this new therapy for keratoconus and other corneal dystrophies.”

Looking to the future, Prof Alió predicted corneal organoids could potentially solve the corneal graft tissue shortages.

He explained the corneal organoids are bio-constructs made with corneal epithelium tissue, stromal laminas from non-human origin, and endothelial tissue shaped with 5D printing techniques to deliver customised corneal optical power.

“This will improve patient quality of life and reduce the economic burden of corneal transplants on healthcare,” he said. “Furthermore, we expect these bio-constructs to provide better therapeutic outcomes over donor corneas, such as avoiding allograft rejection.”

Jorge L Alió MD, PhD, FEBOphth is based at the Universidad Miguel Hernandez, Alicante, Spain. jlalio@vissum.com