epithelial cells. At the fourth month of follow-up, the patients did not show any signs of graft-versus-host disease or abnormal growth. However, one patient presented signs of immunosuppression, although further assessment revealed that the study participant did not follow the instructions on the intake of immunosuppressive drugs. Regardless of this discrepancy, the same patient showed an improvement in vision. There were also signs of improvement in vision in the other eye of the patient, which clearly did not show signs of age-related macular degeneration. The same positive results were observed in the patients with Stargardt’s disease. Current clinical trials are investigating the mechanism behind the positive effects of transplanting retinal pigment epithelial cells. In this comparator study, two arms were created: one group would be examined in terms of the visual gains of the stem cells introduced, whereas the other group would serve as the placebo group.
Another recent clinical trial explored novel options of introducing retinal pigment epithelial cells as cell-based therapy for age-related macular degeneration. The current approach involves the injection of a suspension of cells that gradually reorganized within the retina as a monolayer of cells. The clinical trial thus aims to determine the effectiveness of introducing a preformed monolayer of these epithelial cells, possibly to hasten their capacity to perform their cellular functions within the eye. The monolayer of tissue has been previously described as polarized, thus indicating that it is capable of identifying antero-posterior regions of the eye for further differentiation. Prior to its administration to patients, the polarized monolayer is grown on a polyester substrate that is nonbiodegradable, allowing the transplant to withstand cellular damages from enzymes of the body.
The safety of stem cells derived from bone marrow has also been assessed in various independent clinical trials. One trial tested the efficacy and safety of bone marrow–sourced stem cells in retinitis pigmentosa, whereas another study used these cells for the treatment of early-onset cone–rod dystrophy, which is a genetic disease that is characterized by the deterioration of the cones and rod of the retina. Both studies did not detect any deleterious, structural changes in the recipient eye, as well as any signs of toxicity that could affect the functioning of the retinal epithelia. Several other clinical trials are currently in their design and developmental stages and will most likely be launched in the near future. These studies will provide more information on the efficacy and safety of stem cells in the treatment of eye disorders.
Rhea U. Vallente
Independent Scholar
See Also: Eyes: Development and Regeneration Potential; Eyes: Existing or Potential Regenerative Medicine Strategies; Eyes: Major Pathologies; Eyes; Stem and Progenitor Cells in Adults; Retinal Stem Cells.
Further Readings
Blenkinsop, T.A., B. Corneo, S. Temple, et al. “Ophthalmologic Stem Cell Transplantation Therapies.” Regenerative Medicine, v.7 (2012).
John, S., S. Natarajan, P. Parikumar, et al. “Choice of Cell Source in Cell-Based Therapies for Retinal Damage Due to Age-Related Macular Degeneration: A Review.” Journal of Ophthalmology, v.2013 (2013).
Wright, L. S., M. J. Phillips, I. Pinilla, et al. “Induced Pluripotent Stem Cells as Custom Therapeutics for Retinal Repair: Progress and Rationale.” Experimental Eye Research, v.123 (June 2014).
Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease
Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease
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Clinical Trials, U.S.: Graft Failure, Graft-Versus-Host Disease
Graft-versus-host disease (GVHD) is an immune-mediated syndrome that often occurs after hematopoietic cell transplantation (HCT), and is associated with a higher rate of morbidity, mortality, protracted immune suppression, impaired functionality, and poor quality of life. Though poorly understood, the pathophysiology of GVHD is believed to be due to the interaction of tissue damage and proinflammatory cytokines, donor T cell activation by antigen-presenting cells, and tissue injury by effector T lymphocytes. GVHD occurs in both acute and chronic forms and remains one of the major barriers to improving long-term outcomes in allogeneic stem cell transplant recipients. According to the Glucksberg criteria, which describes severity of GVHD between I and IV (IV being the most severe), acute GVHD (aGVHD) is observed within the first 100 days post transplantation, whereas chronic GVHD (cGVHD) is observed after 100 days post transplantation.
Multivariate analysis has determined that patients who have received mismatched sex or HLA-A, -B, -C, or –DRBI, peripheral blood stem cells, CD3+ replete T cells, who are older, and who have advanced disease are risk factors for the development of GVHD. GVHD is less likely to develop or will be mitigated by ensuring a close donor match. First-line treatment of both acute and chronic GVHD includes the use of corticosteroids (e.g., prednisone) and a variety of immunosuppressive agents; however, this therapy often fails (50 percent), especially when a mismatched donor was used. If the patient fails to respond to steroidal therapy, mortality can be as high as 85 percent. This rate of mortality can be abated by tapering the steroid therapy, particularly in mismatched patients, because it is associated with a desired effect (graft versus tumor).
Glucocorticoid therapy is intended to suppress the T cell–mediated immune attack on host tissues, but in high doses, immune suppression can increase the risk of infection and even cancer relapse, as well as encourage chronic steroid use. Second-line therapies are extensive, have low efficacy, and outcome success is mixed. Therefore, it is important to find alternative targeted therapies, including pharmacologic, biological, or cellular agents that can selectively target immunological pathways and optimize their activity. Stem cell therapy, mesenchymal stem cells (MSCs) in particular, has emerged as a promising alternative since pioneering studies by the Karolinska Institute in treating steroid-resistant aGVHD.
Stem cells are undifferentiated cells that can be divided into two major types: embryonic and adult. Embryonic stem cells are termed pluripotent due to their ability to become any cell type with the appropriate cell signal. Adult cells, which are found in umbilical cord blood, peripheral blood, bone marrow, and organ tissues, are more limited in the types of cells they can become. There are ethical concerns in the experimental use of embryonic stem cells because they are obtained from a developing human, whereas adult stem cell experimentation does not have these concerns. Mesenchymal stem cells, which are obtained in bone marrow, peripheral blood, and umbilical cord blood, appear to have great potential for GVHD and autoimmune disorders due to their immunomodulatory properties. These properties are not well understood, but their ability to secrete soluble factors for cell protection, to home in on damaged areas, and to modulate immune responses are largely believed to be key factors.
Clinical Trials: MSCs to Treat GVHD
Currently, there are a large number of clinical trials evaluating the use of stem cells in the prevention or treatment of GVHD, based on preliminary pilot study results. In a multicenter Phase II trial, 55 patients with severe, steroid-resistant aGVHD were treated with MSCs (median dose 1.4 x 106 cells/kg), expanded in vitro, and in varying doses of cells obtained from HLA-identical sibling donors, haploidentical donors, and third-party donors. These subjects were followed for 60 days. Thirty patients experienced a complete response and nine demonstrated improvement; response was not HLA-match-dependent. Administration of MSCs was deemed safe and the overall two-year survival rate was higher in the patients who were complete responders than those who were partial responders.
Chronic GVHD resembles autoimmune disease in some aspects,
