Emerging technologies on the horizon for corneal diseases

Innovations within the cornea realm are flourishing. In this article, I review emerging technologies to treat corneal diseases.

Corneal stromal stem cells

James Funderburgh, PhD, at the University of Pittsburgh discovered stem cells in the corneal stroma in an effort to use these cells to reduce corneal scarring. In early animal studies and registered human clinical trials in India, Funderburgh and colleagues demonstrated that human corneal stromal stem cells (CSSCs) can regenerate in vitro, and when introduced into the patient’s corneal stroma, these healthy CSSCs can prevent trauma-induced corneal scarring, thereby reducing the need for invasive transplant surgery (Basu et al). One hundred patients have been treated to date. Our current team at the University of Pittsburgh is led by Gary Yam, PhD, and we continue to refine the treatment.

Bioengineered corneal tissue

Several published studies explore the merits of bioengineered corneal tissue made from animal collagen, recombinant human collagen, or combinations of biomaterials and biosynthetics. For example, 10 subjects with advanced keratoconus or corneal scarring were implanted with biosynthetic corneas made of synthetically cross-linked human collagen (Fagerholm et al). This technology has been licensed to Eluminex Biosciences, which has completed enrollment of 85 subjects in a registrational study in China (Semba et al).

LinkoCare is developing bioengineered corneas created from porcine collagen and has conducted a study in which all 14 initially blind subjects achieved best corrected visual acuity of 20/36 at 24 months (Rafat et al).

Precise Bio and Carl Zeiss Meditec are developing laser-induced forward transfer technology, a proprietary bio-printing platform to fabricate a cellular matrix of human corneal tissue, growth factors and cross-linked materials.

The source biomaterials in bioengineered tissue may offer inherent immune privilege, nutritional capabilities and biologic function, but they are also in finite supply, may have limited life cycles and may be expensive to manufacture.

Biosynthetic engineering

EyeYon Medical is developing a biocompatible/biodegradable polyester, polycaprolactone, as a potential source material for corneal tissue for patients with multiple failed corneal transplants or high risk for graft failure. Thus far, approximately 300 patients have been treated by surgeons in Israel, India, Netherlands, France, Germany, Georgia, Singapore, China and Australia. The longest follow-up is 5 years. There have not been any cases of stromal melting or biocompatibility issues to date. Further refinements are anticipated.

Fibroblast growth factor-1

Trefoil Therapeutics is developing an engineered variant of the naturally occurring molecule fibroblast growth factor-1 for use in combination with Descemet’s stripping only procedures. In May 2023, results of a phase 2 study of 49 subjects with corneal edema were presented, showing faster visual recovery in the active treatment group (Baartman et al).

Cell therapy

Cells may be derived from human embryonic stem cells, induced pluripotent stem cells (iPSCs), human umbilical tissue-derived cells, or fully differentiated human cells from various organs or tissues. Stem cells can differentiate into specialized cell types, but their production may pose potential safety risks. By contrast, fully differentiated cells already possess all the essential biologic functions inherent to their specific cell types.

Human corneal endothelial cells (HCECs) do not reproduce in vivo: A person is born with a finite number of HCECs that over time will degrade or deteriorate due to age, disease or surgical trauma. Shigeru Kinoshita, MD, PhD, at Kyoto Prefectural University of Medicine (KPUM) was the first to expand HCECs ex vivo. He developed a combination cell therapy (fully differentiated HCECs and Rho kinase inhibitor) and conducted a first-in-human trial of 11 subjects with bullous keratopathy (Kinoshita et al; Numa et al). Kinoshita and KPUM have out-licensed this technology to Aurion Biotech. More than 130 subjects have now been treated with this cell therapy, including 97 subjects in a phase 1/2 clinical trial in the U.S. and Canada. Aurion has received regulatory and reimbursement approval in Japan and launched commercially in September 2024 under the trade name Vyznova (neltependocel).

Emmecell is developing differentiated HCECs with biocompatible magnetic nanoparticles to treat corneal edema secondary to corneal endothelial dysfunction. In April 2024, Emmecell announced it had completed dosing of approximately 40 subjects in its phase 1 study; some early safety data have been presented (Kunzevitzky et al).

Cellusion has received FDA orphan drug designation for its iPSC-derived corneal endothelial cell substitutes for the treatment of bullous keratopathy, and an exploratory clinical study has been initiated at Keio University in Japan.

In addition to addressing the worldwide shortage of donor corneas, cell therapy may be less invasive and better tolerated than endothelial keratoplasty due to less need for postoperative positioning once the patient returns home. All in all, the horizon for innovations for treating corneal diseases looks promising. I am eager to learn more about the results of the many clinical trials currently underway.

• References:
• Baartman BJ, et al. A phase 2 study of an engineered fibroblast growth factor (FGF) to accelerate visual recovery after Descemet stripping only (DSO). Presented at: American Society of Cataract and Refractive Surgery meeting; May 5-8, 2023; San Diego.
• Basu S, et al. Sci Transl Med. 2014;doi:10.1126/scitranslmed.3009644.
• Fagerholm P, et al. Sci Transl Medi. 2010;doi:10.1126/scitranslmed.3001022.
• Kinoshita S, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1712770.
• Kunzevitzky N, et al. Phase 1 multicenter study of magnetic cell therapy for corneal edema. Presented at: Association for Research in Vision and Ophthalmology meeting; May 1-4, 2022; Denver.
• Numa K, et al. Ophthalmology. 2021;doi:10.1016/j.ophtha.2020.09.002.
• Rafat M, et al. Nat Biotechnol. 2023;doi:10.1038/s41587-022-01408-w.
• Semba C, et al. EB-301: A novel recombinant human collagen-derived biosynthetic cornea as an alternative to human allografts and design of a pivotal registration study (CLARITY). Presented at: Association for Research in Vision and Ophthalmology meeting; April 23-27, 2023; New Orleans.

• For more information:
• Deepinder K. Dhaliwal, MD, LAc, professor of ophthalmology at the University of Pittsburgh School of Medicine, can be reached at dhaliwaldk@upmc.edu.

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Disclosures:
Dhaliwal reports consulting for Aurion, EyeYon and Trefoil and receiving grant support from Kowa.

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