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Comment by Pete Williams 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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Glaucoma is an age-related disease in the majority of patients. Recent data has postulated that accumulated epigenetic changes contribute to, or accelerate, the effects of aging in the cell. This can lead to an increased susceptibility to age- and disease-related insults as well as a loss of protective and regenerative ability with age.

Ksander, Sinclair, and colleagues have questioned whether this process can be prevented or even reversed to provide vision protection / restoration in a mouse model of glaucoma. The collaborative team have previously overexpressed the Yamanaka transcription factors (Oct4, Sox2, and Klf4 (together OSK) but without Myc due to its role in tumorigenesis) delivered to the inner retina via viral gene therapy (packaged within a high titre AAV2.2) to demonstrate a restoration of vision following optic nerve crush or ocular hypertension (induced by microbead administration to the anterior chamber to block IOP outflow) in mice. The current study by Karg and colleagues offers an incremental yet important advance in the current experimental treatment paradigm by using a tet-on system to selectively 'turn on' and 'turn off' the gene therapy under the influence of doxycycline (DOX) provided in the drinking water.

In this study, Karg et al. assessed whether intermittent (denoted 'cyclic OSK' in the manuscript; once at the start of the study, and once towards the conclusion of the study) could provide the same level of visual recovery as continuous OSK (i.e., always on). The Authors demonstrate a robust recovery of vision four weeks post-induction of ocular hypertension with continuous OSK which is partially maintained until 11 months post injection. Recovery of vision is initially matched by intermittent OSK, dropping off by 4 months post induction of ocular hypertension (two months post-DOX withdrawal). Re-administration of DOX at nine months post-induction of ocular hypertension led to a small, non-significant increase in visual function (P = 0.09) which doesn't fully support the authors' conclusions to the manuscript.

Although seemingly positive, many questions still remain. The studies presented here ask additional questions, most notably how does the addition or removal of methyl groups benefit the aging retinal ganglion cell and how does this provide a protection of visual function under stress? The authors note that 'remarkably, the improved visual acuity was even significantly better than the baseline level of vision before the experiment was started' ‐ how is this possible? Is epigenetic reprogramming causing a transient or sustained increase in retinal ganglion cell function that is fully recognized and utilized by the rest of the visual system? Or is this just a function of power and the relatively low n in these groups (n = 4-10 for most experiments)? In this study, there is also no comment on other vital metrics of retinal ganglion cell health and recovery ‐ synaptic and dendritic remodeling, soma counts, and axon numbers in the optic nerve (this last point was also a criticism of the original Nature paper) ‐ do these factor into the visual recovery that this shown in this study? In the microbead model there is significant loss of retinal ganglion cells at this 4 week period prior to the induction of OSK ‐ thus the Authors are seemingly demonstrating increased visual recovery in the absence of retinal ganglion cell repopulation (although this data is missing for any conclusions to be met). This begs the question ‐ what is the mechanism of visual recovery following epigenetic reprogramming?

Several other issues are presented when the longitudinal data is taken into account (in which the authors age the mice to 21 months post-AAV treatment to assess any increased risk of tumor formation). In the initial experiments there is a loss of efficacy of OSK 11-12 months post-injection for which the Author's state 'it is highly possible that at this time, visual acuity is declining, not due to the loss of the OSK reprogramming effect on RGCs, but due to the age-related decline of other retinal layers (e.g., cornea, photoreceptors, retinal pigment epitheliums) that did not receive OSK treatment' yet in the longitudinal data presented there is no age-related structural or visual loss even at the 21 month time point tested (again, is this due to low n or the incomplete analyses of these tissues?). It is worth adding to this statement that the AAV drivers used in these experiments are not retinal ganglion cell specific, so there is likely to be effects that have not been fully assessed in other retinal cell types as well. An important recent study by Yu Wai Man and colleagues demonstrated that AAV2 is promiscuous and was found throughout the visual tract of the uninfected contralateral eye in a non-human primate. Although no tumorigenesis was identified in the initial, basic screening presented by Karg and colleagues (H&E of retinal sections and collapse OCT volumes) future work will have to assess likely the whole mouse for any potential tumors or metastases.

It is important to note that these experiments were performed exclusively on young, female mice. As these are young mice, and the time of treatment intervention is early disease, it is not fully representative of the patients one might see in the clinic who would be appropriate for these treatments (or at least initial clinical trials) ‐ aged and likely close to complete blindness. Thus, it is too early to truly comment whether these treatments, if translated, would be successful in existing glaucoma patients (as good treatments for early disease are already widely available ‐ IOP management in the form of eye drops, laser, and surgery).

Coming off the back of a previous Nature publication (mice) and a widely publicized and well-attended presentation at ARVO 2023 in New Orleans, LA in which similar effects were shown in a non-human primate, there has been ample public interest in these studies. As these studies gain traction in the public eye, we should, at both the level of the researcher and the ophthalmologist, study and question these findings with a rigorous eye and try to see past the longevity hype-machine to the underlying science and how this will benefit glaucoma patients in the future. Rigorous testing and confirmation of findings by other research groups should be the first step towards this.

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