Innovative Cell Therapies in Ophthalmology

Let’s start with a little background; the cells used in cell therapies may be derived from human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), human umbilical tissue-derived cells (hUTCs), or fully differentiated human cells from various organs, connective tissues, and so on. Notably, the merits of stem cells include their capacity to morph and differentiate into specialized cell types, which can then be applied to cell regeneration to address a wide variety of therapeutic categories. The challenges of stem cells? Effectively regulating their differentiation and “turning off” cell reproduction. By contrast, fully differentiated cells already “know” what they are, and so perform all the essential biologic functions inherent in their specific cell types.

The first generation of commercially available cell therapies, including Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, and Carvykti, were autologous and developed by extracting a patient’s T cells from whole blood and modifying them in the lab to attack cancer cells. Specifically, the gene for a special chimeric antigen receptor (CAR) that binds to a certain protein on the patient’s cancer cells is added to the T cells in vitro, grown and returned to the patient by infusion. The resulting CAR-T therapies have been effective but costly to scale. Understanding the practical merits (and limitations) of allogeneic versus autologous cell therapy is essential to evaluate cell production costs and scale, while targeting specific diseases.

In ophthalmology, the death of non-regenerating cells is the cause of many eye diseases. In contrast to other organs, many parts of the eye are immune privileged, which makes allogeneic cell therapy both potentially favorable and scalable.

Cell therapy in ophthalmology initially focused on addressing diseases affecting the retinal pigment epithelium (RPE), retinal ganglion cells (RGCs), and photoreceptor cells (1) to target key retinal indications, such as age-related macular degeneration (AMD) and glaucoma. Other cell therapies have targeted corneal endothelial disease – my own specialty.

AMD
 

Since the 2000s, scientists have been successfully developing the in vitro production of iPSC-derived RPE cells to treat AMD; however, transplanting the cells has proven challenging because of the risks of retinal detachment and/or perforation. Consequently, researchers have sought to adhere the expanded RPE cells to a scaffold – an extracellular “deposit” or hydrogel substrate – to facilitate RPE cell transplant (2). Early safety studies have had favorable outcomes (3). Innovation is ongoing in this area (4), with some studies having commenced as recently as 2022 (5). Other clinical programs are in development, including a phase I study at Astellas (6) and a phase II study at Linneage/Roche (7), among others. Given the large unmet needs of patients with AMD and the sustained level of investment and interest in RPE cell therapy, I believe we will continue to see progress in this area.

Glaucoma
 

As the second leading cause of blindness worldwide, glaucoma is a compelling target for innovations in cell therapy. The promise of transplanting healthy retinal ganglion cells (RGCs) to treat glaucoma is intriguing. Although progress has been made with the in vitro expansion of both ESC- and iPSC-derived RGCs, there are numerous additional hurdles regarding their functional integration in vivo, including retinal localization and neuritogenesis (formation, extension, and branching of neurites), synaptic connectivity with retinal neurons, linear axon growth, and myelination (8) – to name just a few. Nevertheless, there are active RGC/glaucoma research programs at Stanford (9), the University of Pennsylvania (10), and the Wilmer Eye Institute (11), among many others. I believe that these promising preclinical R&D efforts will inevitably lead to further downstream clinical and commercial development.

Corneal endothelial disease
 

Cell therapy targeting corneal endothelial dystrophies has generated more human safety and efficacy data than cell therapy initiatives in other indications. A case in point: data from the first-in-human trial of 11 subjects suffering from bullous keratopathy, treated with fully differentiated corneal endothelial cells produced in vitro in combination with a rho kinase inhibitor, was published in 2018 (12) with five-year outcomes published in 2021 (13). There were no serious adverse events, and subjects have experienced significant, lasting improvements in central corneal thickness and best-corrected visual acuity. The inventor, Shigeru Kinoshita of Kyoto Prefecture University, has licensed this intellectual property for additional clinical and commercial development to Aurion Biotech, which has subsequently performed studies in an additional 67 subjects outside the US. I was one of four US corneal specialists who participated in these studies. Aurion’s data on safety and efficacy was presented at the ASCRS 2023 and AECOS 2023 meetings and was consistent with the initial studies in Japan. For example, at 12 months, average improvement in BCVA was 7 lines (Snellen), with 90 percent of subjects at >3 lines. Early in 2023, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) granted regulatory approval of this cell therapy, making it the first cell therapy in the world to be approved for treatment of bullous keratopathy. A commercial launch in Japan is expected in 2024, with clinical trials in the US starting later this year.

Another corneal cell therapy approach involves the in vitro proliferation of differentiated HCECs with biocompatible magnetic nanoparticles (Emmecell). A phase I study is currently underway to treat corneal edema secondary to corneal endothelial dysfunction in eyes that qualify for surgery involving full-thickness corneal transplantation or endothelial keratoplasty (EK) (14). Select data (unspecified) from nine subjects treated in this study was presented at the 2022 ARVO meeting – at 12 months, subjects ranged between 2–13 lines of improvement and 43 percent of subjects achieved >3 lines (15).

Other companies are using iPSCs to produce HCECs (Ocucell, Cellusion). In 2022, an exploratory clinical study was initiated at Keio University in Japan to examine safety and efficacy of iPS cell-derived corneal endothelial cell substitutes for bullous keratopathy in three human subjects (16).

What’s next?
 

It’s an exciting time for cell therapy in ophthalmology. I believe that the hard work of the last 20 years is already beginning to yield promising results in several different disease indications. And the “virtuous circle” of growing recognition, increasing investments in innovation, and clear progress points to exciting developments in the near future.