Replacement of Damaged Corneal Tissue with Cells Derived from Induced Pluripotent Stem Cells
The transparent cornea covers the eye, and a range of age-related and other issues can cloud that transparency to produce blindness. Engineering corneal tissue is an easier prospect than many other goals in tissue engineering, particular given that transplantation surgery is a good deal easier than is the case for internal organs. This line of research and development has nonetheless proven to have its challenges, such as rejection of transplanted corneal tissue. Work on building engineered corneal tissue has been ongoing for more than twenty years at this point, and has arrived at the point of bioprinted corneas.
Alongside tissue engineering efforts, cell therapy programs have also aimed at repairing the damaged cornea. First generation stem cell transplants, such as the use of mesenchymal stem cells, have shown signs of promise, while the research community aims at the production of cell banks from induced pluripotent stem cells for this use, rather than donor cells.
Today's clinical trial update reports on progress on a middle path between these two approaches, one that has been underway for some years. Here, induced pluripotent stem cells are used to produce sheets of corneal epithelial cells, a structure that is somewhat less than a real tissue, but somewhat more than just a set of cells in suspension. The researchers note that these cells naturally express low levels of surface markers that might provoke an immune response and rejection, a fortunate occurrence that was not deliberately engineered in. So far, this corneal cell sheet seems to produce favorable outcomes when used to replace sections of natural cornea.
Autologous therapy by means of induced pluripotent stem cells (iPSCs) has advantages that include the avoidance of immunological rejection, but it also comes with disadvantages related to the time and expense required for cultivation and the need for tumourigenicity tests. Additionally, from a practical point of view, any instability in the quality of the iPSCs or the graft materials derived from them will lead to the unwanted cancellation of scheduled surgeries. With allogeneic therapy, there is a ready supply of cells, although immunological rejection now becomes an important consideration. However, somewhat unexpectedly, experiments have shown that corneal epithelial cell sheets derived from human iPSCs express lower levels of HLA class I and II compared with somatic cell-derived sheets. Indeed, mixed lymphocyte reaction tests showed no difference in the immune response to iPSC-derived corneal epithelial cell sheets (iCEPSs) between HLA-matched and HLA-mismatched peripheral blood mononuclear cells.
Another important consideration is that the iCEPS construct does not contain immunocompetent cells. It has been reported that a high rate of rejection (about 40%) occurs following an allogeneic corneal limbal transplantation. Previous studies have also indicated that donor-derived Langerhans cells promote early and acute corneal allograft rejection, acting in concert with allogeneic MHC-specific cytotoxic T cells. Graft material for corneal limbal tissue transplantation contains copious antigen-presenting cells, which might increase the probability of a direct pathway to rejection; iCEPSs, however, do not contain immunocompetent cells because only induced corneal epithelial progenitor cells are used to fabricate them. Thus, we hypothesise that HLA compatibility and the use of immunosuppressive agents (above and beyond corticosteroid use) is not necessary for iCEPS transplantation, and incorporate an initial examination of this in our study design. Herein, we report the 52-week follow-up (plus an additional 1-year additional safety monitoring period) of the first-in-human iCEPS transplant surgery in four eyes of four patients with vision loss.