“Alternative” to IPS cells, ICSP, are very cool, but for now a no-go for the FDA

A group of researchers led by Evan Snyder (paper discussed here) published a paper in PNAS on a new type of neural stem-like cell whose pluripotency can be turned ON or OFF by turning the v-myc gene ON or OFF using a conditional system of expression, called a “Tet-ON” system. In this system, tetracycline or its relative doxycycline turn on expression of the viral form of the myc oncogene, v-myc.

High levels of v-myc expression are sufficient to drive the human neural progenitor cells to behave more like stem cells. Snyder’s team calls the cells with the Tet-ON v-myc system “induced conditional self-renewing progenitor” cells, or ICSP, a name easily confused with IPSC (or iPS cells).  The mainstream media played up the angle of ICSP as an alternative to iPS cells, but I’m not convinced.

The paper on ICSP is extremely interesting and the cells very cool, but as someone who has been studying Myc for about 1/3 of my life (wow, hard to imagine), I would argue there is zero chance that ICSP could ever be clinically used. As it turns out, v-myc is just as dangerous an oncogene as any other myc, and perhaps more so.

Some Myc history is required here.  V-myc was the first form of Myc that was identified and it was found as an oncogene in birds. Soon thereafter, the cellular myc proto-oncogene, or c-Myc, was identified and almost immediately after that N-myc was found as a c-myc like oncogene highly amplified in neuroblastoma. Finally L-myc was found amplified in lung cancer.

All these “flavors” of Myc (v-myc, c-myc, N-myc, and L-myc) are potent oncogenes involved in a variety of human cancers. Contrary to some recent arguments, it is NOT clear that L-myc is less powerful as a human oncogene than its other myc family members. There are hints to this effect in model systems, but there can be no doubt that L-myc is an oncogene. Furthermore, v-myc may in fact be a more powerful oncogene than any other myc as v-myc contains potentially super-oncogenic mutations.

What this all means is that the ICSP cells in which researchers can turn v-myc on or off are inherently not suitable for use in human patients.  While it is true that the system by which the researchers controlled v-myc expression seems very clean and they can keep v-myc off, this does not mean the cells are safe. Two key issues come to mind. First, in previous studies there has been some indication that even transient, elevated levels of Myc may be sufficient to cause DNA damage and predispose cells to be cancerous. Second, there is no guarantee that if the ICSP were transplanted in a human patient that the tet-controlled system of v-myc expression would remain intact. In fact, since v-myc makes cells proliferate more, it seems likely that at some future point a transplanted cell would undergo a mutation or epigenetic change that would make v-myc expression always be on. In that scenario, that cell with v-myc ON would proliferate and could easily become a tumor.

I think there’s no way the FDA would ever approve such a system in its current incarnation for regenerative medicine therapy.

But it’s possible that by tweaking the system further, the researchers could make the system far safer. For example, they could add a tandem suicide gene to the system such that if v-myc expression ever turned on in transplanted cells, the suicide gene would also turn on and all those cells would die in the presence of a drug given to the recipient patient after the transplant had already engrafted and helped them.

1 Comment

  1. As I mentioned when I read this paper, I do think that in the long run, some kind of non-pluripotent self-renewing cells will turn out to be superior to IPSC for at least some clinical uses. I definitely agree with you that integrating myc into the cells is not a clinically useful way to induce proliferation, though, even under a dox-inducible system and with characterized integration sites. It’s too risky.

    I hope to eventually see ways of inducing controlled cellular proliferation while avoiding genomic changes….. maybe it’s just a fantasy though. 🙂

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