Allogeneic Ex Vivo Expanded Corneal Epithelial Stem Cell Transplantation: A Randomized Controlled Clinical Trial

Abstract

Limbal stem cell deficiency (LSCD) is a disease resulting from the loss or dysfunction of epithelial stem cells, which seriously impairs sight. Autologous limbal stem cell transplantation is effective in unilateral or partial bilateral disease but not applicable in total bilateral disease. An allogeneic source of transplantable cells for use in total bilateral disease can be obtained from culture of donated cadaveric corneal tissue. We performed a controlled multicenter study to examine the feasibility, safety, and efficacy of allogeneic corneal epithelial stem cells in the treatment of bilateral LSCD. Patients were randomized to receive corneal epithelial stem cells cultured on amniotic membrane (AM): investigational medicinal product (IMP) or control AM only. Patients received systemic immunosuppression. Primary endpoints were safety and visual acuity, secondary endpoint was change in composite ocular surface score (OSS). Sixteen patients were treated and 13 patients completed all assessments. Safety was demonstrated and 9/13 patients had improved visual acuity scores at the end of the trial, with no significant differences between IMP and control groups. Patients in the IMP arm demonstrated significant, sustained improvement in OSS, whereas those in the control arm did not. Serum cytokine levels were measured during and after the period of immune suppression and we identified strongly elevated levels of CXCL8 in the serum of patients with aniridia, which persisted throughout the trial. This first randomized control trial of allogeneic corneal epithelial stem cells in severe bilateral LSCD demonstrates the feasibility and safety of this approach. Stem Cells Translational Medicine 2019;8:323–331

Designing Scaffolds for Corneal Regeneration

“…Some studies have taken limbal cells from the patient's healthy eye, expanded these cells in vitro, and transferred them to the damaged eye using a scaffold. [27] Cells can also be isolated from other tissues in the body or other sources and used to populate scaffolds for corneal stromal regeneration. Bone marrow derived mesenchymal stem cells (BMSCs), [28] adipose derived stem cells (ASCs), [29] and embryonic stem cells (ESCs) [30] and umbilical cord stem cells (USCs) [31] have all been shown to be capable of differentiating toward a keratocyte lineage when cultured under specific biochemical conditions.…”

Corneal Stem Cells as a Source of Regenerative Cell-Based Therapy

“…Based on these data, several clinical trials investigate therapeutic potential of LESCs for the treatment of corneal disorders (Table 1) [46][47][48][49][50][51][52][53][54]. Results obtained in a phase II study, conducted by Zakaria and coworkers [46], showed that standardized, nonxenogenic culture system, reduced manipulation cultivation, and surgical approach are safe and effective in reducing corneal neovascularization.…”

Clinical Outcomes From Cultivated Allogenic Stem Cells vs. Oral Mucosa Epithelial Transplants in Total Bilateral Stem Cells Deficiency

“…The cultivated limbal stem cells were transferred onto the ocular surface on amniotic membrane, which was secured with sutures in all studies with two exceptions, Zakaria et al (27), who secured the graft with fibrin glue, and Ganger et al (29), who used both, either sutures or fibrin glue. In some studies a bandage contact lens was inserted after the transplant (21,24,(26)(27)(28)(29)31) while in other studies a second amniotic membrane was used as a patch (18,22,27,34). One study mentioned using either bandage contact lens or amniotic membrane (20) whereas one study does not mention the use of either (17) In cases of symblepharon, fibrovascular tissue surrounding rectus muscles was dissected in order to achieve normal ocular movement (31).…”

“…Campbell et al (34) conducted a randomized clinical study and distributed the patients into two groups: one which received allogenic corneal epithelial stem cells on amniotic membrane and one which received only amniotic membrane. Both groups received immunosuppression.…”