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Editors Selection IGR 24-3

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Comment by Harry Quigley on:

111960 Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma, Karg MM; Lu YR; Refaian N et al., Cellular reprogramming , 2023; 25: 288-299

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The authors report an apparent improvement in the response to microbead-induced mouse experimental glaucoma after intravitreal AAV2-viral vector expressing three so-called Yamanaka factors (Oct4, Sox2 and Klf4), which are known to induce return to stem-cell state in fibroblasts. These authors previously published data suggesting that there was increased axonal regeneration after optic nerve crush in mice with such expression (Lu et al., Nature 2020; 588: 124-129). Here, they demonstrated that the genetic expression can be controlled by oral exposure to doxycycline, which would provide a safe end to expression if toxicity occurs. The concept is of interest if it can be demonstrated with rigor that neuronal function is retained in the long term, and if survival of retinal ganglion cells (RGC) is enhanced. Neither of these features is demonstrated conclusively here. It will be challenging to determine which of the component genetic alterations are responsible for the reported effects, or if all are required.

There are methodological issues that leave unanswered questions in both papers. Notably, in the Nature paper, the treatment applied seemed to prevent reduction in density of RGC axons, but did not prevent loss of RGC bodies at four weeks after intraocular pressure (IOP) increase. Axons without cell bodies would not provide vision. Axon density data are a poor method to assess survival of RGC axons, as the fibers as well as glial components can lead to no actual change in total fiber number when density is seemingly altered. Instead, density times nerve area provides definitive axon counts.

In the present paper, there are no histological findings to demonstrate that RGC were sufficiently injured such that they later died, even in the non-Yamanaka controls. Rather, the outcomes are based solely on the Optodrum vision method in which how the mouse responds to moving stripes. In treated eyes, 'Remarkably, the improved visual acuity was even significantly better than the baseline level of vision'. No explanation is offered for how vision in treated eyes would be better than normal, but the finding suggests that more control over outcome variation or off-target effects is needed. For some reason, only treated and saline-injected eye vision was measured, not fellow eyes or bilaterally untreated controls. Pattern ERG testing is described in the Methods, but no data are presented to show that pERG was 'improved' or better than control in the glaucoma model, only that it declines with experimental glaucoma as is well-known.

Mice were removed from the study if there was 'edematous cornea', and possibly as a result, the IOPs shown are well below levels typically reported with the microbead model. This leaves open the issue of whether the RGC damage levels in these experiments would be sufficient to equate to other papers on mouse glaucoma, or even that there was histological RGC loss at all in either treated or untreated groups.

The authors should mitigate such stated claims as: 'epigenetic reprogramming of RGCs is a viable and sustainable approach for recovering lost vision in glaucoma', since there is no evidence provided that vision was 'lost', only the possibility that a temporary reduction was reversed. Patients with glaucoma should not be given false hope that vision already impaired by loss of RGCs will be restored by the method presented. Some of the authors report equity in and patents licensed to a commercial firm on this method.

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