A Japanese woman in her 70s has become the first person in the world to receive retinal cells derived from induced pluripotent stem cells (iPS). In a two-hour procedure on September 12, 2014, a team of three eye specialists lead by Dr Yasuo Kurimoto of the Kobe City Medical Center General Hospital, Japan, implanted a 1.3 by 3.0 millimetre sheet made of retinal pigment epithelium (RPE) cells into one eye of this patient, who was diagnosed with age-related macular degeneration (AMD).
iPS cell technology has created significant hope as it comes with any of the ethical or safety concerns that accompany embryonic stem cells.
The procedure was performed at the Institute for Biomedical Research and Innovation, which is adjacent to the RIKEN Center for Developmental Biology (RIKEN), where Dr Masayo Takahashi had managed to reprogram some skin cells from the patient to produce induced pluripotent* stem (iPS) cells, which were later coaxed to differentiate into RPE cells and grow into a sheet for implantation. Once tested, they were ready for the implant surgery.
*'Pluripotent' means able to differentiate into virtually any type of tissue in the body.
The Takahashi protocol involves the establishment of autologous iPSCs from each of the research participants, which are then differentiated into RPE cells using a novel technology that allows these epithelial cells to be transplanted in monolayer cell sheets without the use of synthetic scaffolds or matrices. The cell sheets are shaped into 1.3 × 3 mm grafts and transplanted into the affected site of a single eye, following excision of the damaged RPE and neovascular tissues.
This pilot study follows on extensive preclinical safety and feasibility testing, including evaluations of cell morphology, physiologic activity, gene expression, immunogenicity, and tumorigenesis in rodent and non-human primate models.
Production and validation of the autologous iPSCs and subsequent RPE cell sheets takes approximately 10 months.
RIKEN reported after the surgery that the patient took the surgery well and there was no effusive bleeding or other serious problems during or after the surgery.
This work was preceded by the work done by Dr Yoshiki Sasai, a RIKEN researcher, which led the way to differentiating retinal tissue from stem cells. Obviously, all this work was not possible without the discovery of iPS cells by Dr Shinya Yamanaka, a stem-cell scientist at Japan's Kyoto University who shared the 2012 Nobel Prize in Physiology or Medicine for that work.
Dr Kurimoto performed the two-hour procedure a mere four days after a health-ministry committee gave clearance for the human trial. For the approval, Dr Takahashi and her collaborators had performed safety studies in both monkeys and mice. The animal tests found that iPS cells were not rejected and did not lead to the growth of tumours.
Age-related macular degeneration results from the breakdown of retinal epithelium, a layer of cells that support photoreceptors needed for vision. Currently available drug treatments for this disease focus on inhibiting neovascularization, but do not repair damage that may have already occurred prior to administration. A number of previous studies have tested the use of RPE cells from various sources, such as fetal tissue or unaffected parts of the RPE, for transplantation but have been complicated by problems of immune rejection or the need for invasive harvesting procedures.
The transplant site will be monitored closely for functional integration and potential adverse reactions for an initial intensive observation period of one year, and subsequent follow-up observation for three years. This surgery is not likely to restore this patient's vision. However, scientists around the world will be watching closely to see whether the implanted cells are able to check the further deterioration of the retina, while also avoiding potential side effects such as an immune reaction or inducing cancerous growth.
The future plan is to conduct two more transplant surgeries at intervals of at least eight weeks; the following three will be performed after a preliminary safety evaluation period.
Sources:
1. Nature Journal
2. RIKEN Center for Developmental Biology
3. Time
4. Interview of Dr Masayo Takahashi on ipscell.com
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