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Comment by Keith Martin on:

86863 Reprogramming to recover youthful epigenetic information and restore vision, Lu Y; Brommer B; Tian X et al., Nature, 2020; 588: 124-129

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There has been much recent interest in the idea that an accumulation of epigenetic changes contributes to the effects of aging, including reduction in resistance to injury and loss of regenerative capacity in older animals. But can this process be reversed in order to boost injury resistance and regeneration in the optic nerve and other tissues?

Previous work by Ocampo et al. (Ocampo, A. et al. Cell 2016;167:1719-1733) explored the effects of expressing four genes (encoding MYC, OCT4, SOX2 and KLF4 - the so-called Yamanaka transcription factors) in mice genetically engineered to exhibit accelerated ageing. Turning these genes on for a few days, then turning them off again, led to mice which seemed to age more slowly with epigenetic features expected in much younger animals. However, multiple studies have reported an increased risk of tumor formation when the Yamanaka factors are used for cellular reprogramming.

In the current study, Lu et al. used nicely engineered AAV vectors to deliver Yamanaka factors to the eye by intravitreal injection. They argued that MYC was the most likely factor to cause tumors and was not necessary for the reprogramming effect and therefore used only three transcription factors (OSK) in their experiments. Interestingly, the results seemed to support this idea strongly, with no tumors observed in long-term experiments in mice extending over 15 months.

Expression of the OSK factors in inner retinal cells could be switched on or off by exposure to an antibiotic in a clever use of a conditional expression vector system. The authors interpret their findings as evidence that AAV-OSK promotes axon regeneration after optic nerve injury, and improves some measures of visual function in a mouse model of glaucoma (microbeads injected into the anterior chamber) and in aged mice. The beneficial effects of AAV-OSK seemed to require the DNA demethylases TET1 and TET2. The authors suggest that their experiments indicate that mammalian tissues retain a record of youthful epigenetic information that can be accessed to improve optic nerve function and promote regeneration in vivo.

As is often the case with strong science, the experiments raise at least as many questions as they answer

These findings, published in Nature, are certainly of considerable interest and, as is often the case with strong science, the experiments raise at least as many questions as they answer. The magnitude of the observed regenerative effect after optic nerve crush, with some regenerating axons reaching the optic chiasm but little sign of functional improvement, was similar to or less than what has previously been reported using several other approaches. However, the reported effect in the microbead glaucoma model should be of particular interest to readers of IGR. In this model, IOP is elevated for about three weeks and then returns to baseline, with around 20-30% RGC loss observed during this time. When administered four weeks after IOP elevation, the authors found that their AAV-OSK seemed to improve optic nerve axonal density to normal (without RGC proliferation) and also improve some measures of optic nerve function (PERG and optokinetic responses). The apparent efficacy of a treatment delivered weeks after induction of IOP elevation certainly catches the attention, although it is not clear from the data presented how the suggested reversal of axonal density reduction in particular was mediated. In the authors' defense, whereas axons regenerating beyond an optic nerve crush site are relatively easy to identify, it is much more difficult to identify regenerating axons in glaucoma models. This is an important technical problem in this field and, until we solve it, we should be cautious in attributing any improvements in axon counts and some measures of visual function in glaucoma models to regeneration rather than survival and delayed recovery.

We should be cautious in attributing any improvements in axon counts and some measures of visual function in glaucoma models to regeneration rather than survival and delayed recovery

Overall, this is a challenging and important study that should stimulate even more activity in this exciting field. From the glaucoma perspective, it would be great to see the key findings replicated in other labs and using other injury models and outcome measures. As ever, the relevance to human disease remains to be seen at this stage, but there are plenty of intriguing possibilities.

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