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Comment by Derek Welsbie 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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For patients who have already lost vision from glaucoma, options are very limited and usually center around consultation with a low vision specialist. While dramatic lowering of the intraocular pressure (IOP) may lead to a very modest improvement in some patients, for the vast majority there are no treatments to restore vision. Several groups have shown that retinal ganglion cells (RGCs) injured in glaucoma enter a phase of axonal degeneration that precedes cell death, indicating the presence of injured-but-not-yetdead cells. Thus, in order to restore vision, there have been a number of strategies developed (with limited effectiveness) to regenerate axons in an attempt to reconnect these injured cells. In this article, Lu et al., from the labs of Bruce Ksander, Meredith Gregory- Ksander, Zhigang He and David Sinclair, demonstrate that epigenetic reprogramming of RGCs can lead to robust axon regeneration and partial restoration of vision, including in a mouse model of glaucoma.

It is well-known that aging is a key risk factor for the development and worsening of glaucoma. Moreover, while developing, immature RGCs can extend axons, this capacity is greatly reduced in adult neurons. The question that Lu et al. addressed was whether RGCs could be partially reprogrammed, such that they de-age and increase their regenerative capacity, but not totally de-differentiate and lose their RGC identity. To test this, they turned to the Yamanaka factors, Myc, Oct4, Sox2 and Klf4, which convert cells into induced pluripotent stem cells (iPSCs). To avoid complete reprogramming (and to avoid the use of a potent oncogene), the authors excluded Myc and expressed Oct4, Sox2 and Klf4 cDNAs together using adeno-associated virus (AAV) and a tetracycline-regulated system. The viruses were injected intravitreally and the effect on RGC cell death and axon regeneration was tested using the mouse optic nerve crush (ONC) model. Typically, there is profound cell death by two weeks and no meaningful axon regeneration. However, in RGCs expressing Oct4, Sox2 and Klf4, the team saw improved RGC survival coupled with axons regeneration at least to the level of the chiasm. Interestingly, by giving tetracycline on different schedules and altering the timing of expression, they found that the three genes had to be expressed after injury, suggesting that the effect was to reverse injury-induced changes.

Since Yamanaka factors are known to change the epigenetic marks regulating gene expression, the authors measured DNA methylation across the genome. In response to ONC, they saw a change in the pattern of methylation, including increased methylation of ribosomal DNA, which indicates accelerated aging. In contrast, RGCs expressing Oct4, Sox2 and Klf4 had a nearly complete normalization of the DNA methylation pattern. Moreover, consistent with the model that partial reprogramming was removing the injury-induced methylation, the phenotype was dependent on the presence of cellular demethylation enzymes like TET1 and TET2. The expression of Oct4, Sox2 and Klf4 even reversed normal age-related vision loss in mice and was associated with a reversal of the methylation aging clock.

Clinically, it will be important to determine the abundance of injured-but-not-yet-dead RGCs that might be amenable to such a strategy and to figure out the timing of expression in RGCs at different stages of injury and regeneration

Finally, the authors turned to the mouse microbead model of glaucoma. After four weeks of elevated IOP, there was typical RGC cell death, axon loss and decreased vision (as measured by optomotor responses). The authors then injected the virus after the injury and showed unprecedented improvement of axon density and a partial restoration of visual function. Paradoxically, there was not a concomitant increase in RGC survival, leaving open the question how axon density increased. Clinically, it will be important to determine the abundance of injured-but-not-yet-dead RGCs that might be amenable to such a strategy and to figure out the timing of expression in RGCs at different stages of injury and regeneration.

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