The waiting game: First human iPSC clinical trial on hold

Author: Guest, 09/01/15


Nicole Forgione is a post-doctoral fellow working in the Fehlings group at the Toronto Western Research Institute. Currently she holds a Toronto Western Research Institute Fellowship to support her work on cell-based regenerative therapies for traumatic spinal cord injury. Nicole earned her BA from Wilfrid Laurier University, where she studied English Literature and Biology. She went on to complete her MSc and PhD at the University of Toronto. Follow Nicole on Twitter @DrNForgione.


Picture_of_brown_eyesAlmost a year ago, Nature reported that researchers at the RIKEN institute in Japan had transplanted induced pluripotent stem cells (iPSCs) into a human recipient for the first time.

This technology has the power to effectively hit rewind on the cellular differentiation process. Adult cells, like the ones that make up skin, can be reprogrammed into pluripotent cells that have the ability to generate any cell type in the body. The potential of iPSCs to generate patient-specific cells for transplantation, which reduce the risk of rejection, has contributed to the incredible push to move iPSCs into clinical trials.

Not surprisingly, this groundbreaking work has garnered a great deal of attention from observers. Dr. Masayo Takahashi is the lead investigator on this trial aimed at testing the ability of patient-derived iPSCs to treat age-related macular degeneration (AMD). AMD is a leading cause of visual impairment in the elderly. Under normal conditions, photoreceptor cells in the retina, known as rods and cones, process light entering the eye. These cells translate visual information into impulses that travel, via the optic nerve, to the visual centres in the brain.

Individuals suffering from AMD, and other retinal disorders, experience degeneration of photoreceptor cells resulting in progressive vision loss and eventually blindness. The proper functioning of the retina is dependant on a specialized layer of cells, known as retinal pigmented epithelium (RPE), that lies outside of the retina. Damage to the RPE is a hallmark of AMD and contributes to the loss of photoreceptors in the retina.

The approach in this trial was to generate iPSCs from skin cells taken from patients with AMD. Using specialized cell culture methods, the iPSCs were differentiated into sheets of RPE cells that were transplanted to the retina.

According to Paul Knoepfler—a stem cell researcher and blogger—the scientific community, and the world, will have to wait to see if this treatment will live up to the hype. Dr. Knoepfler reports in his blog that the RIKEN trial has been halted due to the identification of potentially harmful mutations in iPSCs. The concern is that transplanting cells that are genetically unstable could lead to uncontrolled cell growth and tumour formation. Initially, the nature of these mutations was unclear. In a series of comments on the original blog post, Dr. Takahashi explains that a total of six mutations were found in iPSCs prior to transplantation into a second patient. These mutations were not present in the genome of the patient, indicating that they arose during the reprogramming process. Dr. Takahashi maintains that the likelihood of tumour formation due to these mutations is low. Interestingly, she cites regulatory changes as the main reason for halting the trial.

In light of safety concerns surrounding iPSCs, it is worth putting these latest developments into the context of other advancements in retinal regeneration. A recent Business Insider article reports that, in the near future, these emerging treatments could be commonly used to restore vision in the majority of patients.

In the past decade gene therapy, cell-based therapy and visual prostheses have become three approaches to treating vision loss that have reached the clinical trial phase. Each of these strategies comes with benefits and drawbacks.

Visual prosthetics – In the current season of the sci-fi series Orphan Black, a visual prosthetic device is used to restore sight in the damaged eye of one of the main characters. This pop culture portrayal signals that this technology has made it to the mainstream; however, the potential of these devices is overstated in the show. In reality, visual prosthetics can’t actually restore vision to normal. Instead, they can provide patients with some improvements that could help them live more independently.

Currently, the Argus II is the only FDA approved visual prosthetic device on the market for severe retinitis pigmentosa. The Argus II works by sending data, from a small video camera mounted on a pair of glasses, to a microchip that is implanted next to the retina. Data about the user’s surroundings are translated into electronic pulses that are delivered directly to retinal cells.

Second Sight, the company that manufactures the Argus II, has plans to begin testing this device in patients with AMD. Visual prostheses offer a cell-free method for treating vision loss, and therefore do not come with the risk of immune rejection or uncontrolled cell growth. However these devices are very costly, with a price tag of US$144,000. Even with this expensive device, patients must undergo extensive training to learn how to interpret the signals generated by the device and navigate their environment.

Gene therapy – The basic idea behind this approach is to replace defective, disease-causing genes with functional ones. There are a number of clinical trials in progress looking at the benefits of gene therapy for different retinal disorders. The most promising results have been observed in leber congenital amaurosis (LCA)1, 2. One such Phase I clinical trial demonstrated that gene therapy has no adverse effects and, in some cases, improves vision in LCA patients.

While LCA is rare—affecting 1 in 1,000,000 live births—it is an early onset condition, and thus has received a lot of attention. Furthermore, LCA is the perfect candidate for a gene therapy approach because scientists have pinpointed a single defective gene—RPE56—that is responsible for the condition.

AMD can also be treated with gene therapy. In the later stages of the disease, referred to as wet AMD, the abnormal growth of blood-vessels causes damage to the RPE and retina. An innovative gene therapy approach to treating wet AMD involves blocking the genes responsible for over-growth of blood vessels. A key requirement for successful gene therapy is the sparing of functional visual cells. In cases where degenerative processes have destroyed the majority of these cells, gene therapy is unlikely to have an effect. Moreover, it is possible that degenerative processes could continue even after gene therapy is delivered, thus negating any therapeutic benefit.

Cell-based therapy: iPSCs are the most recent in a long line of stem cell types that have been tested in humans for the treatment of retinal degeneration. Human embryonic stem cells (hESCs) have been used in clinical trials for AMD. Early results from one of these trials, published this year, shows that these cells are safe and help to improve vision.3 The moral, ethical and logistical issues surrounding the use of human embryos are the most significant drawbacks to using this particular cell type. hESCs are allogenic, meaning they cannot be obtained from the patient and instead are derived from a donor. Therefore, hESCs come with the risk of being rejected by the recipient. Autogenic iPSCs, derived from the patient, could circumvent the challenge of immune rejection. Yet, in her comments on Dr. Knoepfler’s blog post, Dr. Takahashi reveals that the next step will be to use allogenic iPSCs. At first glance this seems like a puzzling reversal. However, Dr. Takahashi and her team have discovered that RPE cells derived from allogenic iPSCs do not trigger a significant immune response in animal models. Moreover, this approach would allow more patients to be treated. This change in direction has yet to be highly publicized, and could have important implications for the use of iPSCs in humans.

This leaves us with the question, why the focus on iPSCs given that there are alternative approaches?

As a developmental biologist by training, the most compelling reason I can think of for studying iPSCs is their unparalleled potential to allow scientists to ask fundamental questions about cellular identity. Scientists have been investigating the determinants of cell fate since the 1950s. Building on the work of Briggs and King4, the somatic nuclear transfer experiments carried out by Sir John Gurdon provided the first clear evidence that adult cells could be reprogrammed into immature cells. With his work on iPSCs, Shinya Yamanaka opened the next frontier in this field.

Given the tremendous potential of iPSCs in the arenas of both therapeutics and basic science research, where does the emergence of these most recent safety concerns leave us?

I would argue that these latest developments surrounding the RIKEN trial are an important step along the way, not only in the clinical translation of this technology, but also in understanding the basic biology of iPSCs. Any scientist (myself included) working with stem cells in the field of regenerative medicine shakes in their boots at the mere mention of phrases like “harmful mutations” or “uncontrolled cell growth.” The fear is that reports of safety concerns will scare people away from pursuing this technology. However, these problematic results are just as important as the successful results. They in fact provide avenues for more investigation instead of limiting them.

The hope now is that further study of the mutations in the RIKEN iPSCs will help us to refine the reprogramming process to avoid future pitfalls.



  1. Maguire, A.M., High, K.A., Auricchio, A., Wright, J.F., Pierce, E.A., Testa, F., Mingozzi, F., Bennicelli, J.L., Ying, G.S., Rossi, S., Fulton, A., Marshall, K.A., Banfi, S., Chung, D.C., Morgan, J.I., Hauck, B., Zelenaia, O., Zhu, X., Raffini, L., Coppieters, F., De Baere, E., Shindler, K.S., Volpe, N.J., Surace, E.M., Acerra, C., Lyubarsky, A., Redmond, T.M., Stone, E., Sun, J., McDonnell, J.W., Leroy, B.P., Simonelli, F. and Bennett, J. (2009). Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374, 1597-1605.
  2. Hauswirth, W.W., Aleman, T.S., Kaushal, S., Cideciyan, A.V., Schwartz, S.B., Wang, L., Conlon, T.J., Boye, S.L., Flotte, T.R., Byrne, B.J. and Jacobson, S.G. (2008). Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 19, 979-990.
  3. Schwartz, S.D., Regillo, C.D., Lam, B.L., Eliott, D., Rosenfeld, P.J., Gregori, N.Z., Hubschman, J.P., Davis, J.L., Heilwell, G., Spirn, M., Maguire, J., Gay, R., Bateman, J., Ostrick, R.M., Morris, D., Vincent, M., Anglade, E., Del Priore, L.V. and Lanza, R. (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, 509-516.
  4. Briggs, R. and King, T.J. (1952). Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proc Natl Acad Sci U S A 38, 455-463.
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