Age related macular degeneration (AMD), a significant cause of blindness in older people, has attracted substantial attention as a condition to be tackled in the first trials of regenerative medicine using cells derived from Pluripotent Stem Cells. Lines of these cells, first isolated as ‘embryonic stem (ES) cells’ from the pre-implantation stages of early embryos, have the ability to differentiate into any cells types found in the adult human body. Subsequently, it was shown that similar cells, so called ‘induced pluripotent stem (iPS) cells’ could be obtained by reprogramming somatic cells to an early embryonic-like state.
Under the right culture conditions, both ES and iPS cells differentiate into retinal pigment epithelial (RPE) cells, the cells that support the photoreceptors of the retina and are lost in AMD. A paper just published in the New England Journal of Medicine (Mandai et al. 2017) reports the first clinical trial of RPE cells derived from iPS cells to treat AMD. Although only a single patient was treated in what was primarily a phase 1 safety trial, the report highlights issues that will have to be addressed more generally as regenerative medicine develops.
Phase 1 trials of ES cell-derived RPE cells have also been reported (Schwartz et al. 2015, Song et al. 2015) and similarly found no significant adverse effects due to abnormal cell proliferation or tumor formation, suggesting that the approach is intrinsically safe. However, because they are derived from early human embryos, ES cells pose ethical difficulties for some people, particularly in some countries, while there are concerns that transplantation of allogeneic will require long term immunosuppression which may cause other problems for the treated patients. The use, by Mandai et al (2017), of autologous iPS cells derived from somatic cells of the patient, to produce the RPE cells for transplantation alleviates both the ethical concerns about the use of embryos and the need for immunosuppression. Consequently, the first clinical transplantation of iPS cell-derived RPE cells represents an important milestone.
One of the issues raised in this report, however, is that iPS cells from one prospective patient were found to carry several mutations not detected in that patient. Although, there was no strong evidence to indicate that these particular mutations would cause a problem, on the precautionary principle, RPE cells from those iPS cells were not used. However, ES and iPS cells do commonly acquire genetic variants during culture, probably because some mutations offer the undifferentiated stem cells a growth advantage (ISCI 2011). These were first detected as karyotypic changes, for example, gains of chromosome 17 or 12. It would be relatively straight forward to avoid using cell lines carrying such gross changes but, with ever finer genetic analysis, all ES and iPS cells will inevitably be found to carry genetic variations of some description. It will, then, be essential to develop a framework to decide which mutation present an unacceptable risk and which are acceptable given the specific context such as the type of cell to be transplanted, the age of the patient and the site of transplantation. This is an area of current active debate, and will eventually require an international consensus as the pace of trials develop, something that was recently discussed at a meeting organized at the Jackson Laboratory in Bar Harbor by the International Stem Cell Initiative (http://www.stem-cell-forum.net/initiatives/isci/).
Amps, K., et al. (2011). “Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage.” Nat Biotechnol 29(12): 1132-1144.
Mandai, M., et al. (2017). “Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration.” N Engl J Med 376(11): 1038-1046.
Schwartz, S. D., et al. (2015). “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies.” Lancet 385(9967): 509-516.
Song, W. K., et al. (2015). “Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients.” Stem Cell Reports 4(5): 860-872.