iPSC Therapy in Macular Degeneration
Case Study:
Autologous Induced Stem-Cell–Derived Retinal Cells
for Macular Degeneration
Mandai, M., Watanabe, A., Kurimoto, Y., Hirami, Y., Morinaga, C., & Daimon, T...Takahashi, M. (2017).
Overview
Researchers at Riken Center for Developmental Biology in Japan have been investigating the use of iPSCs to treat macular degeneration. This paper reports the results of two clinical trials on iPSC-derived retinal pigment epithelium as a treatment for macular degeneration.
Background
Figure 1
Retina is the light-sensitive tissue lining at the back of the eye. It consists of neural cells called rods and cones that turns light into electrical signals and the transmit the signals to optic nerves for colored image generation in the brain. Retinal pigment epithelium (RPE) lines behind rods and cones and serve as a protective layer for the retinal cells and the vasculature that support these cells. Figure 1 shows a zoomed-in picture of the retina, RPE, rods and cones and the macula. The macula is a small area on the retina that is about 5.5 mm in diameter. It facilitates central vision and is important in daily activities such as reading, driving, and focusing on a certain object. For a review on eye anatomy, click here.
What is age-related macular degeneration?
In age-related macular degeneration (AMD), pathologies develop in RPE, which impair its function as a support to the neural cells. As a result, rod and cones die and the patients partially or completely lose central vision. There are two kinds of AMD, wet or dry AMD. Dry AMD is a chronic disease that develops over time. In dry AMD, metabolic products deposit behind retina and cause scarring and thinning of the retinal tissue. There is currently no cure to dry AMD. On the other hand, wet AMD is an acute disease that may develop in days or weeks. In wet AMD, there is an overgrowth of vasculature into the retina, which causes bleeding and affects neural cell function.
The most common treatment for wet AMD is the injection of anti-vascular endothelial growth factor (VEGF). VEGF is a growth factor that supports the growth of blood vessels. In the case of wet AMD, anti-VEGF is injected directly into the patient's’ eye to stop the overgrowth of vasculature. However, instead of curing the disease, this treatment only alleviate the symptoms. Once the patient stops receiving anti-VEGF injections, AMD will recur. Other treatments such as the surgical procedure that removes the disease-affected RPE also prove to have low efficacy and may cause potential damage to the unaffected area. Therefore, scientists have been looking at ways to treat wet AMD by generating healthy RPE to replace the damaged tissue in patients. It has come to light that iPSCs may be a promising cell source for the regeneration of RPE.
Methods
In this clinical trial, skin fibroblasts were taken from the patients and were reprogrammed into iPSCs by exposing the fibroblasts to transcription factors. iPSCs were cultured on scaffolds to form sheets of RPE tissue, which was implanted into the patient’s eye. The objective of this clinical trial is to 1) assess the safety of iPSC-derived RPE cells and the iPSC-RPE sheet transplant procedure and to 2) investigate the efficacy of iPSC-RPE transplant in treating wet AMD.
The clinical trial started in summer of 2013. Two patients participated in the clinical trial. Patient 1 was a 77-year-old Japanese women who had suffered from wet AMD in both eyes since 2010 and received a total of 13 injections of anti-VEGF. She enrolled in the study in 2013 and received iPSC-RPE transplant in her right eye in 2014. Patient 2 was a 68-year-old Japanese man. However, he had to drop out of study because the iPSC-derived RPE underwent mutation, which caused concerns. Figure 2 shows the iPSC-RPE sheet implant in Patient 1’s eye. The white arrows indicate the location of the graft. During the surgical procedure, the membrane with the abnormal growth of vasculature was removed from Patient 1’s right eye, while the iPSC-RPE graft is implanted at the center of vision.
Figure 2: iPSC-RPE graft
Results
Safety
iPSC-derived RPE cells showed DNA packing and gene expression that resemble those of human RPE tissue. They also expressed RPE-specific gene markers that are consistent with those of the actual RPE tissue. That is, iPSC-derived RPE cells have similar genetic material as the RPE cells in human body. By performing genome-sequencing, it was determined that iPSC-derived RPE cells were not tumorigenic and did not carry cancer genes.
Up until 1 year after the procedure, there was no incident of graft rejection, severe complications, unexpected cell growth or tumorgerinicity. Therefore, it was concluded that the use of iPSC-derived RPE cells for treatment is safe.
Efficacy
Figure 3 shows the growth of tissue before and after the surgery. In Figure 3a, the leftmost image shows a large bright spot indicated by the black asterick. This was the tissue affected by the overgrowth of vasculature. After the surgery, this piece of tissue was removed and the normal vasculature underneath became visible. The white arrows indicates the locations of the graft. In Figure 3b, the large white mass circled by the dotted line represents the overgrowth of vasculature. We can see that this white mass disappeared 1 year after the surgery and RPE-like cells formed, as shown by the yellow line. Figure 4 shows a time-lapse image of of the cross-section area around the graft. The yellow lines indicate the length of the graft. the iPSC-RPE sheet seemed to expand slightly over time.
Figure 3: iPSC-RPE implant before and after surgery
Figure 4: Time-lapse image of iPSC-RPE graft
At 1 year after the surgery, there was no recurrence of abnormal growth of vasculature in the patient’s eye and the patients did not need to receive anti-VEGF injections. However, there was no improvement in visual ability, though the patient’s eyes did start to fix more at the center of vision.
It was concluded that the removal of the area of abnormal vasculature growth seemed to be a wise step and that the graft potentially exerted effect on the disease-affected tissue and prevented the recurrence of vasculature overgrowth. In addition, the flattening of the graft over time might be due to the growth of RPE cells in the graft and their incorporation into native tissue.
Conclusion
Although there was no improvement in the patient’s visual ability, abnormal vasculature growth stopped after the surgery without anti-VEGF injections, which indicates that the iPSC-RPE transplant might have produced some therapeutic effects. In addition, the iPSC-derived RPE cells seemed to have incorporated into the native tissue and showed decent growth in the eye. These results suggested that iPSC-derived RPE tissue transplant might have the potential to treat wet AMD. More clinical trials need to be done to further analyze its safety and efficacy.
Reference
Figure 1 credit to <http://www.closerlookatstemcells.org/stem-cells-and-medicine/macular-degeneration>
Mandai, M., Watanabe, A., Kurimoto, Y., Hirami, Y., Morinaga, C., & Daimon, T...Takahashi, M. (2017). Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. New England Journal of Medicine, 377(8), 792-793. doi:10.1056/nejmc1706274
<http://www.nejm.org/doi/10.1056/NEJMoa1608368>
Figure 2,3,4 Credit to this paper
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