FDA OKs risky, pioneering OSK rejuvenation trial with Sinclair’s ER-100

The FDA has cleared a trial of ER-100 from Life Biosciences for eye rejuvenation.

In the trial, ER-100 will deliver inducible expression of the three reprogramming factors. OCT4, SOX2, and KLF4 are colloquially known together as OSK. This trial is an extension of the work of Harvard professor and longevity enthusiast David Sinclair.

The hypothesis here is that partial reprogramming of cells in the damaged eye could lead to eye rejuvenation. The bigger hope is that similar approaches could rejuvenate other organs more generally. And the most aspirational of all is the idea that some similar technology could reverse the decline of entire aging organs. Or even rejuvenate the whole aging body. In that way, people could have greatly extended healthspans.

Admittedly, these ideas are potentially exciting. However, in my view it’s more than a bit oversold within the longevity field. If we just focus on the more concrete trial at hand for ER-100 in the eye, it is still an extraordinarily high-risk study.

ER-100 trial and efficacy challenges

Life Biosciences, co-founded by Sinclair, will test OSK partial reprogramming in a small number of participants with one of two eye conditions. They’ll either have open-angle glaucoma or non-arteritic anterior ischemic optic neuropathy (NAION).

Ganglion cells are the main target of ER-100, which is a viral approach. The overall notion seems to be to generate “younger” versions of these cells that can somehow spark eye rejuvenation. To my knowledge, this will be the first in vivo partial reprogramming trial of this kind, which gives a certain coolness factor.

However, I’m skeptical it’ll both work and be safe for several reasons.

One challenge is that ER-100, even under ideal reprogramming conditions (which no one knows in the human eye), will not lower the eye pressure of glaucoma. So, if there is rejuvenation, it may not last. For NAION, which typically is a one-time ischemic event, there could be microenvironmental conditions that are problematic. The hostile environment could be toxic to the newly reprogrammed younger cells and could inhibit their functions. This means that ER-100 could face some of the same challenges as emerging potential cell therapies for brain conditions. For example, in Alzheimer’s the toxic tissue microenvironment may kill or render new (e.g., transplanted) or rejuvenated cells inactive.

Overall, just the right efficacy is going to be very difficult to achieve for ER-100.

Then there are challenges associated with viral gene therapies (ER-100 is delivered virally) more generally like delivery efficiency. Further, what if ER-100 ends up in other eye cells?

Background on reprogramming

Stepping back for a moment, early on with such trials including the new one for ER-100, the focus will be on safety. Let’s go through some brief background. It should also be helpful when we go on to think about potential safety concerns.

The original Yamanaka protocol for cellular reprogramming included something called OSKM, with the fourth factor being the proto-oncogene MYC or the “M” in the acronym. My lab regularly did this kind of reprogramming. Then teams found that reprogramming to make iPS cells could work without MYC (using just OSK) but is much less efficient. Both with and without MYC, of course, the goal is to make iPS cells. This only makes sense to do in the lab.

In contrast, in a clinical setting with in vivo reprogramming, researchers don’t want to make iPS cells in the body. It’s too dangerous and might not be useful. Hence, the idea of partial reprogramming was born, where you just make the target cells younger (developmentally, that is) without changing them all the way back into iPS cells.

For example, in the eye, you might make retinal ganglion cells, photoreceptors, or other cells change into younger versions of themselves. They retain their identity rather than turning into iPS cells. The hope appears to be that these now younger cells are then more functional and may trigger better healing somehow. It’s not entirely clear how.

To do this partial reprogramming of cells, in a sense you have to dial down the reprogramming strength. In the ER-100 trial that more nuanced outcome is hoped to be accomplished in patients with just OSK and only with transient pulses of expression.

Risks of the ER-100 trial

In mice, reportedly these kinds of partial reprogramming methods can in certain cases lead to the desired partial reprogramming apparently without teratoma or other tumor formation, but it’s tricky. Sometimes teratoma were formed in related studies. Also, what works in mice often doesn’t in people. The biggest worry about the new trial is still that patients could get cancers or benign teratomas in their eyes, which would be catastrophic in either case.

Notably, such outcomes in the eye are at least much more likely to be self-contained (and can be more readily monitored). Partial reprogramming of internal organs like the diseased or aging liver, kidney, heart, etc. is a much bigger challenge (plus cells in that context cannot be easily monitored) and has more risks.

The partial reprogramming in human eyes or other tissues needs to be incredibly precise. I feel like what needs to happen in the ER-100 trial participants is hitting a tiny bull’s eye with a bazooka. Even if it’s more like a precise laser and it’s just transient OSK, the tool could overwhelm the target tissue and miss the hoped-for outcome.

You don’t even have to accidentally make some iPS cells to have troubles. Reprogramming that’s not quite right could still form various tumors. Even without generating obvious tumors, OSK pulses could lead to other, unpredictable and harmful changes in cells or other areas of eye tissue.

The other thing about the ER-100 approach is that it’s not actually treating the health condition in the eye directly. It’s turning on complex gene expression programs in surviving cells that are hoped to make younger cells in the affected area, which in turn might spur regeneration…or problems. To get the former desired outcome, there are a series of events that have to happen just right.

Is it time for a trial?

With all of this in mind, are there enough preliminary data to warrant a human clinical trial?

It’s unclear.

Mouse research has been published, but the non-human primate work (which also apparently was fairly encouraging as reported at meetings) appears not to have been published.

Presumably, FDA reviewers, who recently allowed the IND to clear for the trial, have seen all of it though and felt okay about it. With today’s FDA, I have to say I feel less sure about the top leadership than the experienced reviewers who go over IND applications. The reviewers are generally outstanding and much more data-focused. However, leadership can pressure or overrule reviewers. I’m not saying that happened here at all, but today’s FDA just seems less predictable.

I asked well-known stem cell biologist Jeanne Loring for her thoughts on the trial:

“Reprogramming factors are very potent, and we don’t know how much expression leads to making cells tumorigenic. It is well known that the inducible systems are leaky- never fully silenced, so my concern is that this treatment is likely to be unsafe and cause tumors.”

I tend to agree with Jeanne on this.

Broader perspectives

Beyond Life Bioscience, there are also a growing number of other biotechs in this space. I wrote about Shift Bioscience and their molecule SB000, whatever that is. Other biotechs are hoping to set similar sets of reprogramming dominoes in motion via their own approaches to partial in vivo reprogramming.

As a stem cell biologist, I find reprogramming of all kinds, especially to try to treat diseases, fascinating. We just have to keep it real. A lot can go wrong.