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The Current State of Therapeutic Development Involving Induced Pluripotent Stem Cells

A little more than a decade has passed since the development of a simple cell reprogramming approach that reliably created pluripotent stem cells from ordinary somatic cells, known as induced pluripotent stem cells. These stem cells are very similar, near identical in fact, to the embryonic stem cells that were previously the only reliable source of cells capable of forming any cell type in the body. Arguably the most important aspect of induced pluripotency is not the promise of the ability to generate patient-matched cells for regenerative therapies and tissue engineering of replacement organs, but rather that it is a low cost, robust procedure. It is easily adopted by any laboratory capable of basic cell biology operations, without the requirement of any complicated new knowledge or techniques. It thus spread very rapidly, and many labs were working on further development within a year or two of the first paper published on the topic.

Nonetheless, the highly regulated (and thus enormously expensive) process of clinical development proceeds at its own slow pace, no matter the ease or difficulty of the underlying technology. Trials of regenerative therapies based on induced pluripotency are taking place, but only in recent years, and only a few of them. Beyond the regulatory burden, this is also a symptom of a broader hold-up in stem cell therapies in general, in that the cells transplanted by the vast majority of first generation therapies do not survive and engraft in large numbers. Benefits are transient, achieved through the signals provided by the transplanted cells, rather than any other work accomplished by those cells. The research community is in the midst of establishing techniques to ensure that stem cells survive and then behave correctly in patient tissues, to not only deliver beneficial signals for the long term, but also provide a supply of daughter somatic cells to help restore lost tissue function. This second phase of stem cell therapies will be far more beneficial than the first, once underway in earnest.

Increasing Number of iPS Cell Therapies Tested in Clinical Trials

In a surgical procedure last month, neurosurgeons implanted 2.4 million cells into the brain of a patient with Parkinson's disease. The cells - derived from peripheral blood cells of an anonymous donor - had been reprogrammed into induced pluripotent stem cells (iPSCs) and then into dopaminergic precursor cells, which researchers hope will boost dopamine levels and ameliorate the patient's symptoms. The procedure is the most recent attempt by clinicians to test whether iPSCs can treat disease. In recent years, scientists have launched several clinical studies to examine their efficacy in heart disease and macular degeneration of the eye. And others are exploring ways to turn the cells into treatments for everything from endometriosis to spinal cord injury.

So far, only a handful of patients have undergone iPSC-based treatments. In 2014, a woman with macular degeneration of the eye received a transplant of iPSC-based retinal cells derived from her own cells. The woman treated showed no apparent improvement in her vision, "but the safety of the iPSC-derived cells was confirmed." Last year, five patients were treated for the same eye condition with iPSC-derived retinal cells, which were taken from different donors. One of them patients developed a "serious," but non-life-threatening, reaction to the transplant, forcing doctors to remove it. More clinical studies are underway. Next year, heart surgeons plan to implant sheets of iPSC-derived cardiomyocytes into the hearts of three patients with heart disease, and other researchers hope to treat six more patients with Parkinson's disease by 2022. These are all in the earliest phases of testing.

By now, researchers have figured out how to coax iPSCs to grow into most known cell types. But to get these cells to take on the roles of mature cells in a new tissue environment is another issue. In the heart, for instance, researchers have found that new stem cells have to be electrically aligned with the other cells. How to integrate the new cells so they will survive in injured or diseased tissue is another question. "Do you need a special matrix, a gel, a patch, an organoid, to ensure the success of these cells long term? These challenges are faced in all the organs."

Another concern researchers have frequently raised are the immunosuppressive drugs that patients require if the iPSCs are derived from cells other than the patient's own. The patient with Parkinson's, for instance, will be on immunosuppressants for a year, possibly making the patient less able to fight off infections and cancer. But despite the risks, many researchers have opted to use allogeneic stem cells - those from a donor - foremost because the approach will save time, cost, and labor when the time comes to scale up such treatments for commercialization. The possibility to create "off the shelf" iPSC therapies has also attracted industry, not just academics. For instance, Cynata Therapeutics recently concluded a Phase I trial using iPSC-derived mesenchymal stem cells to treat graft-versus-host disease (GVHD). Conveniently, immune rejection isn't an issue with mesenchymal stem cells because they don't express the donor-specific antigens that trigger rejection.

Developing off-the-shelf treatments is also vastly more cost effective than maturing iPSC-derived cells for individual patients. Personalized T-cell immunotherapies, two of which have been recently FDA-approved, can nearly $500,000 per patient. This is one reason why several groups are developing banks of iPSCs that can be used to develop regenerative therapies at scale. For instance, the Japanese government decided to put around $250 million towards developing an iPSC stock for biomedical research. The donors from whom these cells are derived were carefully selected with immune compatibility in mind: the bank is designed to encompass a diverse set of commonly present human leukocyte antigen (HLA) types, so that they are broadly representative of the majority of the population.

Comments

> the cells transplanted by the vast majority of first generation therapies do not survive and engraft in large numbers. Benefits are transient, achieved through the signals provided by the transplanted cells, rather than any other work accomplished by those cells.

Probably, I have said it in other comments here before. The fact that the transplanted cells don't survive might be a blessing in disguise. The ESC, when injected in-vivo, readily form teratomae (one of the test to confirm that the embryonic stem cells actually work). And that's not exactly the result we want for retinal and brain treatments.

On the other hand, this shows how little do we understand the cell and tissue processes at this point. Luckiliy the graft survival can be tested in cheap murine models without touch the pricey human procedures.

For now , culturing personalized IPSC is expensive but it doesn't have to be with proper protocols and kits , when done at scale the cost could go down significantly. Probably to 300 dollars, per culture but only when adopted on a massive scale.

And for the off-the shelf IPCS to work they have to find a way to avoid the immune rejection. Either by modifying the culture not to express most of the the antigens and matching them to the individual immune profile ( It is amazing that the immune system is so specific that it can reject transplants from siblings). When look at the challenges faced by producing off-the shelf cells, i would rather concentrate on reducing the cost of the personalized ones unless we want to benefit only from the pro-repair signalling of the graft...

Posted by: cuberat at December 4th, 2018 5:51 PM

Why are so expensive the personalized stem cell therapies? Is it a technical problem? A regulatory problem? A logistics problem?

Posted by: Antonio at December 5th, 2018 3:14 PM

@Antonio: Allogeneic cell lines are just another drug: manufactured at some centralized facility and then stored for later use. Everyone gets the same thing, so maximum automation, economies of scale, and logistical optimization. Personalized therapies have to be produced to order, require much more hands on cell-wrangling, and are generally a pain from both logistical and regulatory standpoints. It is harder to do quality control, as every patient has to have their own quality control exercise, for example.

Posted by: Reason at December 5th, 2018 4:53 PM

Mmm maybe someone can automate the process, like we do now with dyalisis.

Posted by: Antonio at December 6th, 2018 3:11 AM

@Antonio

Yes, that's why I said that they don't have to be that expensive but unless you have a magic kit to do the whole extraction, select and culturing thing it will require more effort than a simple off-the shelf selection. On the other hand, when the stem cells will be used on larger scale a lot of cost saving measures will be found and implemented.

Posted by: cuberat at December 6th, 2018 12:18 PM

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