Process of reprogramming stem cells for clinical use is unlikely to lead to cancer-causing mutations in patients

Researchers from The Scripps Research Institute and the J. Craig Venter Institute have assessed various iPSC reprogramming methods for safety in cell therapy.

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Feb 25, 2016
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A new study led by scientists at The Scripps Research Institute and the J. Craig Venter Institute (both CA, USA) have demonstrated that programming pluripotent stem cells for clinical use is unlikely to lead to cancer-causing mutations in patients. The findings were recently published in Nature Communications.

Induced pluripotent stem cells (iPSCs) can differentiate into any kind of cell in the body and hold potential for wound repair or diseases such as Parkinson’s and multiple sclerosis.

The new study focused on the safety of iPSCs in human patients. There are concerns that the stresses of inducing pluripotency may lead to deleterious DNA mutations in iPSC lines, which would compromise their use for cell therapies.

“We wanted to know whether reprogramming cells would make the cells prone to mutations,” commented Jeanne Loring from The Scripps Research Institute and leader of the new study. “The answer is ‘no.’”

"The safety of patients comes first, and our study is one of the first to address the safety concerns about iPSC-based cell replacement strategies and hopefully will spark further interest,” added Schork Nicholas J. Schork, study co-leader and professor and director of human biology at J. Craig Venter Institute.

To produce iPSC lines, scientists must reprogram an adult cell, such as a skin cell, to express a different set of genes, which can be accomplished using viruses as delivery vehicles or with molecules messenger RNAs (mRNAs).

The team carried out a comparative analysis of three popular iPSC generation protocols: integrating retroviral vectors, non-integrating Sendai virus and synthetic mRNAs. Each method was assessed for safety and their potential to induce cancer-causing mutations. While the researchers noted some minor benign alterations in the iPS cells, none of the methods led to significant mutations.

“The methods we’re using to make pluripotent stem cells are safe. We need to move on to developing these cells for clinical applications,” stated Loring. “The quality control we’re recommending is to use genomic methods to thoroughly characterize the cells before you put them into people.”

The team warns that while iPSCs don’t trigger cancer-causing mutations during reprogramming, harmful mutations could potentially accumulate at a later stage when iPSCs proliferate in vitro. Loring concluded that scientists must analyze their cells for these mutations before using them in therapies.

Sources:

Bhutani K, Nazor KL, Williams R et al. Whole-genome mutational burden analysis of three pluripotency induction methods. Nature Communications, doi:10.1038/ncomms10536 (2016) (Epub before print); http://www.scripps.edu/news/press/2016/20160219loring.html

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Elena Conroy

Contributor, Future Science Group

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1 Comments

Go to the profile of James L. Sherley, M.D., Ph.D.
James L. Sherley, M.D., Ph.D. almost 2 years ago

This report is unfortunately tone deaf in so many ways that it is hard to know where to begin to review its basic errors in the treatment of the issue addressed. But let us begin:

1. Let us begin with the obvious problem that, since iPSCs are defined operationally by their formation tumors after transplantation into mature tissues, they are therefore tumor-forming whether or not the authors find cancer risk mutations.

2. Although the authors acknowledge that they do find a lot of iPSC-associated genetic defects, including occasional cancer risk variants, they don't count this as a problem. But they are only looking at a few nicely behaved clones. Who knows, even their selection of a few similar clones (there being no mention of a random basis for choosing clones for analysis), may heavily bias their findings. When patients receives millions of cells in proposed transplantation therapies, in addition to their inherent tumor forming activity, at the high rates of mutation observed - either from the initial divisions of future iPSCs or during their expansion for therapy - there will be ample opportunity for even more cancerous variants to be transplanted or generated by expansion within patients afterwards.

3. Related to #1 above, cancer risk defects need not be evident in gene mutation analyses. Epigenetic defects have also been reported during iPSC development. Witness the finding that the p53 growth regulation pathway is often disrupted during iPSC production, but this important cancer risk pathway is not always activated via gene mutations in the p53 gene itself.

4. Since the iPSC induction genes (or their encoded proteins) inherently produce cells that grow well in culture, other gene mutations that would do the same in the absence of the iPSC inducers (i.e., in cancer risk genes) will have no selective advantage in culture. Hence, such gene mutations will not be found at higher rates than the average rate of mutation in any given gene that is not under selective pressure in culture.

So the authors' assertion that they provide evidence that iPSCs could be safe for stem cell transplantation medicine is surprisingly obtuse to their findings and possible explanations for their findings that they do not consider in their report. In actuality, they affirm once again that iPSCs, even produced by three different procedures, all have a high rate of gene mutation, a very dangerous prospect of stem cell transplantation medicine.

In any case, even if iPSCs were free of mutations, they and their differentiated mature derivatives cannot provide the asymmetric self-renewal required for long term reconstitution of mature organs and tissues. Only natural distributed stem cells (also know as adult tissue stem cells) can meet this essential need for stem cell transplantation medicine...and compared to iPSCs, they are essentially mutation-free. [Sherley, J. L. (2014) “Accelerating Progress in Regenerative Medicine by Advancing Distributed Stem Cell-Based Normal Human Cell Biomanufacturing,” Pharm. Anal. Acta 5: 286. doi: 10.4172/2153-2435.1000286]

James L. Sherley, M.D., Ph.D.
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Asymmetrex, LLC
jsherley@asymmetrex.com