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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I’m not a scientist in the sense of the hard sciences (yep, I’m but a lowly MSW.) But I do know history and religion. WHY should we need to have gone all the way back to ““clinical trials in progress or beginning”? Is it scientific, or is the situation more like this: Answering that question isn’t likely to qualify me or anyone else for the MacArthur Genius Award. Every step of the way, it has been necessary to fight the political right and the religious right for hESC research. How much of the switch to IPSC’s is about superior science, and how much is the tacit admission that the fight was exhausting and time-wasting and thank God there’s a way to avoid it. (and the necessity for it was morally indefensible)? Could we have had hESC based treatments years ago if this fight hadn’t happened? Those are the questions that are completely avoided here. Probably correctly so, too, and yet these questions exist, and they are so important in terms of societal attitudes and perceptions surrounding stem cell based research. Thoughts?
@bystander- aha, I see what you mean.
I’m tempted to say: “but they’re liars, and I’m not!” But I DID NOT actually say that- don’t quote me!. I’m basing my optimism on the fact that fetal tissue trials resulted in reversal of symptoms in some, but not all, of those treated. Also, it’s encouraging (to me) that about a dozen independent research groups are testing human pluripotent stem cell-derived dopamine neurons in animal models and, in one case, a new clinical trial. The independence of these groups is an important factor to me.
Would Macchiarini or Anversa have been justified in saying that the clinical promise of stem cells was coming true, based upon “clinical trials in progress or beginning”? (Neither got quite so far as making claims for iPSC specifically AFAIK, but still.)
Despite everything I have seen transpire, I would still like to believe that there will be meaningful (and mechanistically sound, pipe dream though that might be) scientific progress in cellular reprogramming that will yield tangible and reproducible clinical benefits.
Nonetheless, I have lost my patience for incautious-at-best clinical claims.
I think it is coming true. Why do you think not?
“In the last several years, the clinical promise of iPSC-derived cells is coming true, with clinical trials in progress or beginning […]”.
I just spent over an hour articulating my full reaction to this in the larger context of the whole stem cell field and all that I have seen transpire therein. I felt satisfied with the ~550 words I eventually produced, but decided they would be a derailment and unhelpful here.
Perhaps I will find another place to say all that came to my mind.
For now, I’ll just say that my conclusion emphasized this point:
I really, REALLY wish for more care with phrases like “the clinical promise … is coming true.”
Hi Paul-
Both female hESCs and iPSCs at least partially reactivate their second X chromosome some of the time. The “controversy” about this is due to different methods of analysis, timing of the assessment during expansion of hPSCs, and size of individual datasets. We did a comprehensive study a few years ago: https://www.ncbi.nlm.nih.gov/pubmed/22560082 and discussed it in a review article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229506/. Some iPSC clones reactivated the 2nd X within about 20 passages, and others did not.
Curiously, partial reactivation of the second X in iPSCs doesn’t seem to affect anything about the cells, including differentiation, at least in the derivatives we’ve studied.
To answer your question directly, we still don’t know.
(let me know if you want to write a grant app on this…)
George,
there is a phenomenon that was called “epigenetic memory”, which referred to the regulatory factors that control what genes are active. Some researchers believed that if a skin cell is reprogrammed, it will be pluripotent but retain a preference for becoming skin…same for blood cells and so on. Even if there does seem to be a preference, it is transient..a “short term” memory, and if the differentiation methods are good, it doesn’t change what the cells become.
Our DNA methylation studies showed that there is complete overlap between hESCs and iPSCs. Since we are all mosaic, our cells differ in their genomic sequence a little bit. Since each iPSC line is a clone of a single reprogrammed adult cell, it is possible to pick up an iPSC line that has DNA variants that are suboptimal for use in transplantation therapy, but we check for that.
Hi Jeanne,
What’s the status of research on X chromosome reactivation in female hIPSCs and does that present a challenge?
Paul
Hi Dr. Loring, some while ago I read of the phenomenon of genetic memory in iPSC – where does this play in, if you say that ESC and iPSC are identical? Also, are iPSC not by default an “older” and can it be assumed that everything about that iPSC has been somehow turned over and purged? Thanks for your insight. GS
James: There are challenges with getting pluripotent stem cells to develop beyond the fetal stage for some derivatives. However, we can mature dopamine neurons into mature post-mitotic neurons that make synapses and release dopamine when stimulated.
Also, as part of our quality control, we do whole genome sequencing, so we can detect all mutations, and we assess the cells’ functional maturation. Since we expand our cells so little, there is less chance of induction and selection of the mutations that are associated with cancer. For example, we detected p53 mutations in expanded hESC populations for the first time in 2015 (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118307); since then several other groups have found that p53 mutations are selected for in multiple pluripotent stem cell lines when they are greatly expanded.
Hi Jeanne,
I wanted to throw out a few topics/Qs for the conversation which might get things focused on the value add here:
– Do you have any views on the proposed reimbursement payment model for bespoke Autologous cell therapy treaments that has been circulating for awhile but recently highlighted by BlueBird’s 5yr plan based on the drug’s continued performance > https://www.pharmacist.com/article/biotech-proposes-paying-pricey-drugs-installment
– In terms of manufacturing clinical doses of Autologous therapies I’m sure it’s something you and your team are now well versed in, considering your near term plans to start the clinical translation of the program. Given the resources applied and the current development of the Auto CAR-T manufacturing arena, do you see parallels with these first movers in standardizing the process for your specific productization once it’s ready to be commercialized?
– Your point about immunosuppression is indeed a significant challenge for most early Allo Pluripotent programs. You mentioned in a previous Niche thread (https://ipscell.com/2018/09/quick-qa-with-viacyte-ceo-on-crispr-stem-cell-work/) that work is underway on addressing Allo Therapeutic Immunogenicity through the use of gene editing (Universal Cell tech and the like), to potentially avoid a patient’s rejection of foreign [Allo] cell transpants. Will this technology address the issue you’ve raised or will there still be some immunosuppression requirements needed? Also, not all Allo treatments require immunosuppression – for instance there was some discussion on whether the Eye, Brain (CNS), being immunoprivildged sites, don’t require the same or even any immunosuppression regimes (yet to be tested in the trials but suggested). Also it’s probably worth noting that Adult Allo based MSCs and the 1st Pluripotent derived Allo MSC program for GvHD don’t use immunosuppression. As far as I’m aware Cynata isn’t forecasting to need any for their pipeline using Pluripotent MSCs.
Cheers
Michael,
I’ve addressed your questions in an email to you.
Jeanne
Thank You Jeanne, very nice post. Seems forever ago we were first thinking about using hESCs primarily for organ/tissue replacement. Almost 20 years later, the real legacy of hESC research is the understanding of pluripotency and the foundation created on how to guide these toward lineage-specific cells. Once iPSCs came on the seen, the valuable work and protocols already created with hESCs expedited the application of patient-derived iPSCs to understand disease by creating novel patient-specific cellular models and assays for therapeutic drug development, as well as possible cellular replacement therapy.
Thanks, Steve! The time we spent studying hESCs hasn’t been wasted!
Dr. Loring:
Thank you for your informative article.
How do you and others pursuing iPSC-derived cell therapy think about the problems of differentiation limited to fetal cell physiology and the inability of differentiated cells, whatever their stage of differentiation, to provide tissue cell homeostasis like natural adult tissue stem cells (which of course also have their technical challenges for developing efficacious cellular therapies).
Also, though you screen for mutations that might cause cancerous cell proliferation, do you also screen for mutations that might compromise the desired function of iPSC-derived cells?
Thank you,
James at Asymmetrex
“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”.
My understanding of the Parkinson’s Disease Induced Pluripotent Stem Cell transplant performed in Japan in 2018 is that the patient was and is required to take immune suppression drugs. However, the cells given to him were taken from an anonymous donor. So this treatment for Parkinson’s in Japan was more of an allogeneic as opposed to an autologous procedure. A few questions.
1. Why not use the Parkinsons patient’s own skin cells from the beginning making it more of an autologous procedure?
2. Why induce autologous stem cells to an embryonic like state to begin with?
2A. Wouldn’t it have been safer to use a patients autologous stem cells placed into the dopamine producing areas of the brain without inducing them to a pluripotent state further avoiding the chance for tumorogenesis/rejection? If no then…..
3. Has their been any sort of clinical or pre-clinical work utilizing autologous stem cells for use in the dopamine producing area of the brain to better treat or cure Parkinson’s Disease?
Douglas- good questions. Here are answers:
1. Why not use the Parkinsons patient’s own skin cells from the beginning making it more of an autologous procedure?
That is exactly what we are doing.
2. Why induce autologous stem cells to an embryonic like state to begin with?
Inducing the cells resets them so they can make dopamine neurons, and methods for reprogramming to pluripotency are well established and safe. The only other way to make differentiated cell types is to direct convert adult cells into another cell type using transcription factors. But that is problematic- it’s inefficient and cells often don’t respond the way that is expected.
2A. Wouldn’t it have been safer to use a patients autologous stem cells placed into the dopamine producing areas of the brain without inducing them to a pluripotent state further avoiding the chance for tumorogenesis/rejection? If no then…..
The dopamine neurons have been tested in hundreds of animal models and don’t make tumors. Whole genome sequencing, along with other genomic assays assures that they don’t carry harmful mutations.
3. Has their been any sort of clinical or pre-clinical work utilizing autologous stem cells for use in the dopamine producing area of the brain to better treat or cure Parkinson’s Disease?
Not in humans yet, but patient-specific iPSC-derived dopamine neurons reverse disease in animal models of PD.
Thank you for your reply, Dr. Loring.
The risk of tumorigenicity is no different for hESCs or iPSCs. We find no tumors from our cells in animal models, and we do whole genome sequencing to make sure they haven’t acquired any mutations that might cause abnormal growth. Another advantage of autologous iPSCs is that we don’t need to culture them for very long- so there are fewer cell divisions and a lower chance of mutations taking over the cultures compared to scaling up a single cell line to treat everyone.
Nice post. What about tumorigenicity from iPSC?