What can you do with cells that live forever and can make every cell type in the body? The answer is: remarkable things, as new reports of clinical trials using cell types derived from pluripotent stem cells indicate.
Pluripotent stem cells are either derived from embryos donated from IVF procedures (human embryonic stem cells- hESCs) or from cells provided by a person, usually blood or skin (induced pluripotent stem cells- iPSCs). The stem cells are never used for transplantation; instead, they are differentiated into a cell type that is useful for therapy.
As you know from Paul’s reporting, hESCs have been used to generate cell types that are currently in clinical trials: pancreatic islet cells to treat Type I diabetes, glial cell precursors to treat spinal cord injuries, and retinal pigment cells to treat age-related macular degeneration (AMD).
There are two kinds of pluripotent stem cells; why choose hESCs instead of iPSCs? After an enormous effort to prove their safety to the FDA, the company Geron initiated the first clinical trial using hESCs in 2009. Very few others wanted to start all over with the FDA to get approval of iPSC-derived cells, so most projects chose to use hESCs.
But around 2012, some researchers began considering the use of iPSCs instead of hESCs for development of their planned therapies. From my lab’s first publication on genomic analysis of hESCs and iPSCs in 2008, we were certain that hESCs and iPSCs were the same cell type. But convincing fellow scientists of this was difficult. I remember a conference in around 2011, where I asked for a show of hands from the few hundred people in attendance if they agreed that hESCs and iPSCs were the same…all but 2 said no!
In the last several years, the clinical promise of iPSC-derived cells is coming true, with clinical trials in progress or beginning using iPSC-derived mesenchymal stem cells, NK cells, retinal pigment epithelium, and dopamine neurons. Paul’s recent summary of news in this area is here.
But so far only one patient has benefited from the unique advantage that iPSCs have over hESCs. iPSCs can be autologous, which means they are made from one individual, then the differentiated cells can be transplanted to the same individual without need for immunosuppression to prevent them from being rejected. This approach was pioneered by Masayo Takahashi, who transplanted autologous iPSC-derived RPE cells to an AMD patient in Japan.
Yesterday, in a landmark publication, Kapil Bharti from the NIH and his collaborators further opened the door to autologous iPSC therapy. The key to using autologous iPSCs is to have robust differentiation methods, and great methods for making sure that each patient’s cells are of consistent quality. Bharti’s group accomplished this by developing reproducible differentiation methods and clever quality control assays for assessing the functionality of the cells in culture; their assays were designed to show safety of the cells without having to test every cell line in animals.
I’m excited about Bharti’s project because my lab has been developing autologous iPSC-derived cell therapy for another disease: autologous dopamine neuron replacement therapy for Parkinson’s disease. Like the AMD project, we have developed methods to make the same high quality differentiated cells from multiple patient’s iPSCs. We have developed novel predictive genomic methods to make sure that the neurons will function correctly after transplantation. Like the recently published work, we routinely analyze the patient cells for mutations that might compromise their safety, using whole genome sequencing.
It is my hope that experiences like Takahashi’s and Bharti’s will pave the way to using the unique properties of iPSCs to develop safe effective autologous cell replacement therapies, just as Geron’s trial paved the way for hESC-based therapies.
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