Cultured Cells and Inhibitor May Restore Cornea in Patients with Bullous Keratopathy

Brianne N. Hobbs, OD;  Robert Fintelmann, MD


May 19, 2017

Impressive Study Results

The cornea is not forgiving.

Multiple physiologic systems have to be operating near perfection for the cornea to maintain its transparency. A layer of particular importance in this effort is the corneal endothelium, which actively pumps water out of the cornea. If the corneal endothelium is substantially compromised, it results in bullous keratopathy. Historically, treatment of this condition has required donor corneal tissue coupled with invasive surgery, but recently a new therapeutic option has surfaced: cultured corneal endothelial cells.

A group of researchers in Japan investigated whether cultured human corneal endothelial cells injected into the anterior chamber could restore endothelial function and corneal transparency.[1] Eleven patients (mean age, 64.4 years) diagnosed with pseudophakic bullous keratopathy who had no detectable corneal endothelial cells were enrolled. Each patient had a corneal thickness > 630 µm and visual acuity less than 20/40.

The degenerated endothelial cells were surgically removed, and then cultured human endothelial cells were injected into the anterior chamber. A rho-associated protein kinase inhibitor (ROCK) was injected along with the cultured cells to promote cell survival and adhesion. After the injection, patients lay in a prone position for 3 hours. Systemic and topical glucocorticoids as well as antibiotics were administered after the injections.

Although the study was small, the results were impressive. All 11 eyes obtained a corneal endothelial cell density > 500 cells/mm2, with 10 eyes achieving 1000 cells/mm2 and six eyes exceeding 2000 cells/mm2 at 24 weeks post-injection. An improvement in both corneal structure and function was demonstrated, with a corneal thickness < 630 µm achieved in 10 of the 11 eyes and 82% of eyes having a two-line improvement in visual acuity. A sustained therapeutic effect was achieved; after 2 years, all 11 eyes maintained corneal transparency.

One patient developed steroid-induced glaucoma, but no other major systemic or ocular adverse effects were reported.

Cultured Cells: Promise and Concerns

The potential to encourage replication among cells previously thought incapable of doing so is exciting. The ability to introduce cells cultured outside the body via a minimally invasive technique reduces the need for donor tissue and avoids many of the complications associated with corneal transplants. This study is clinically relevant because in addition to anatomical improvement, participants sustained functional gains over 2 years.

The promise of cultured corneal endothelial cells does not come without concerns, such as the fate of those cells that do not attach to the cornea, because of the risk for ectopic tumor formation. Serology and systemic health evaluations were completed in participants and no abnormalities developed over the course of the study, but that evidence is insufficient to definitely exclude the possibility of tumor development, owing to the small sample size and limited study duration.

It is also difficult to discern which element of the treatment was actually responsible for the increased corneal cell density. The authors hypothesized that the cultured cells were primarily responsible for the restored endothelial function, but acknowledged that the action of the ROCK inhibitor could have also prompted the recipient's own endothelial cells to replicate. Regardless of the mechanism, the treatment was largely successful in attaining meaningful gains in endothelial function and visual function.

The ability to dramatically and rapidly increase endothelial cell counts would be revolutionary.

The ability to dramatically and rapidly increase endothelial cell counts would be revolutionary. Even partial restoration of endothelial function would potentially allow patients with bullous keratopathy to be candidates for other treatments that improve vision, such as contact lens fitting and cataract surgery, which are currently contraindicated in low endothelial function.

The safety of cultured endothelial cells with ROCK inhibitors must be confirmed, but this proof-of-concept study should be considered a success.

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