iPS cell clinical trials – Are we ready?

by Alexey Bersenev on October 10, 2012 · 2 comments

in Uncategorized

Induced pluripotent stem (iPS) cell technology just won a Nobel Prize. Not a surprise. It was expected and well deserved!

How do I feel about iPS cell field? A buzz. A passion. An obsession. Fast and furious. Remarkably reproducible. Impressive. Today, everybody seem to be inspired by a Nobel and started to talk about clinical future again. I’m going to skip drug discovery, toxicology and disease modeling today. I’d look what we have on iPS cell “therapeutic plate”. The topic, which gives some chills to everyone, who involved in stem cell research and cell therapy. This post is rather brief summary than deep thoughtful analysis. But give me a feedback and I’d dig.

Current status
At the moment we don’t have any clinical trials assessing iPS cells as therapies. All query results, which pop up in databases, referred to isolation of iPS cell lines from patients, banking and studying “disease in the dish”. No therapies guys. None.

To date, I was able to track 14 iPS clinical trials in NCT database and 2 trials in UMIN-CTR (Japanese) database. The typical example of such iPS trial:
Development of iPS From Donated Somatic Cells of Patients With Neurological Diseases.
The first iPS cell trial was actually launched in Japan in 2009 – Pathological analysis of hereditary deafness using iPS cells.

A buzz
Earlier this year, Japanese researchers announced rather ambitious plans for the world’s first iPS cell therapeutic clinical trial:

Dr. Masayo Takahashi at RIKEN, Japan, has announced at the 11th Congress of the Japanese Society for Regenerative Medicine that her research team will start, in 2013 at the earliest, first clinical trials for treatment of age-related macular degeneration by transplantation of retinal pigment epithelial cells induced from human iPS cells.

Yet another high profile proposal (from Stanford University) is dedicated to treatment of skin disease – epidermolysis bullosa by iPS cell-derived keratinocytes. Reportedly, this trial could be launched in 2014.

One more, from recent news:

Prof. Hideyuki Okano at Keio University will start a clinical study on patients with spinal cord injuries in about five years. In an experiment, he found that marmosets paralyzed in all four limbs were able to walk about six weeks after he transplanted nerve cells created from iPS cells.

Finally, we can’t miss this intriguing announcement from Robert Lanza:

Science behind and safety data
So, the first proposed trial suppose to test iPS cell-derived Retinal Pigment Epithelial (RPE) cells in macular degneneration. Reportedly, RIKEN’s team is going to use Yamanaka’s technique – the one, which includes c-myc. Indeed, Takahashi’s team made RPE cells from from monkey’s iPS, using Yamanaka’s factors. Unfortunately, they didn’t report transplantation and long-term safety data. Is Yamanaka’s method the safest one? Far from it! Why would they pick it for a trial? I think it’s not even clinically suitable! Why not integration-free methods?

The risk of tumorigenicity is the biggest issue in iPS cell-based therapeutics translation. Let’s see how safety issues could be addressed in RPE cell therapy. RIKEN’s team proposed to use a few assays to detect residual undifferentiated iPS cells in final RPE cell product. Other groups didn’t observe any tumors in mouse preclinical models for iPS-derived RPE cell transplantation. What we’re missing here is the long-term observations in large animal models (monkey?) of iPS-derived RPE cell therapy.

About Stanford trial:

The Stanford team has not yet published any papers validating their proposal. But in December, Tolar reported the first evidence that the approach could work. He and his colleagues created iPS cell lines from two children and one teenager with a recessive form of EB. They then ‘fixed’ the iPS cells by inserting a working version of the defective collagen gene associated with the disease and showed that these gene-corrected cells could form structures resembling skin that deposited collagen in the same areas as healthy tissue (J. Invest. Dermatol. 131, 848–856, 2011).

Yet another protocol for generation of iPS-derived keratinocytes from patients with epidermolysis bullosa was published recently. But, again, not by a Stanford group.
So, no preclinical data on epidermolysis bullosa from Stanford.

Ok, let’s look at other preclinical data on iPS cell therapy. First of all, we have to focus on large animal models and long-term observations. If you look at literature, you can see almost zero of such studies. I was able to find only 2 very recent studies in cardiology. German group tracked human iPS cells in large animal model of myocardium infarction. 15 weeks after transplantation 100 millions of undifferentiated iPS cells didn’t produce any tumors in pig myocardium under immunosuppression. In cardiomyopathy model, iPS (generated by Yamanaka’s method) cell-derived cardiomyocytes survived in pig hearts up to 8 weeks and didn’t form any tumors.

More safety concerns
Many professionals think that, at the moment, we’re absolutely not ready for iPS cell therapeutic trials. Unfortunately, almost nobody speaks about it publicly. Yes, we have a lot of safety issues with iPS cells and their derivatives. Intriguingly, genomic instability observed in vitro, doesn’t necesserily have a direct correlation with tumorigenicity in vivo. Nobody knows why. Well, animal models never perfect.

Paul Knoepfler is the only one stem cell researcher, who speaks publicly and openly about issues with iPS cells. You can read his excellent posts here, here, here and here.

What he said about Japanese trial proposal:

This is both exciting, but also potentially very risky if not flirting with disaster.

It would be tragic if the excitement and creativity exploding from iPS cells became diminished in the future by a rush to the clinic that harmed patients.

Some concluding thoughts
First, I’d like to say that clinical readiness is one of the biggest stem cell misconceptions. Second, I’d like to conclude, that right now we are not ready for iPS cell therapeutic clinical trials. More likely we will not be ready in the next year. We are lacking of preclinical data from large animal models and long-term observations. Let monkeys and pigs live 2-5 years with iPS! We don’t know how to deal with iPS cell genomic instability. We don’t have good assays to detect transformation events in iPS cell products. We don’t have validated methods for separation of residual undifferentiated iPS cells from their “therapeutic progeny”.

Now, regarding RIKEN and Stanford proposals. I think, we have to acknowledge that the eye and skin is the way to go! Two good targets to start. Japanese group is much closer to the goal. They published some data. But, the absence of long-term “monkey data” and use of Yamanaka’s method, could be worrisome. One year from now? I’d say 1-2. Still very risky game! Stanford group – no data, no discussion! I don’t think they will get close by 2014.

Finally, we are lacking open discussion about all issues that I’ve mentioned above. I think, one of the reasons for lack of open debate is biases and potential conflicts of interest, which iPS cell researchers could have. While it’s hot and sexy it feeds us well!

One final point. As a cell manufacturer and trialist, I’d stay skeptical about “bright therapeutic future” of iPS cells. Even if some trials will succeed in 7-20 years from now, iPS cell will fail on the market and will experience the lack of widespread adoption.

{ 2 comments… read them below or add one }

Lee Buckler October 11, 2012 at 2:51 am

I say there are way too many unknowns about these cells for the FDA to clear a trial to proceed any time in the next 2 years at minimum. If people start using them clinically. This will happen in other regulated ountries (likely several) before it happens in the US. Likely Japan and S. Korea first then perhaps Catholic Europe.


Michael January 12, 2013 at 12:29 pm

A bit cryptic but don’t forget ACT’s WSJ article on their upcoming iPS trial, http://online.wsj.com/article/SB10001424127887324296604578177420241514666.html .. platelets seem like the low hanging fruit of iPS


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