This is an exciting time for regenerative medicine, especially as it relates to ophthalmology. Diseases of the retina and optic nerve have long been considered treatable but incurable. Anti-VEGF therapy revolutionized our field by enabling vision improvement through resolution of cystoid macular edema or subretinal fluid in conditions such as diabetic retinopathy, neovascular age-related macular degeneration, and retinal vascular occlusion. But when retinal cells die, irreversible vision loss occurs. Because retinal neurons and retinal pigment epithelium (RPE) are not regenerated in mammals (including humans), retinal neurodegenerative diseases yield permanent functional impairment. Regenerative medicine approaches to replacing lost RPE and retinal neurons are on the brink of changing that dogma. Human clinical trials investigating subretinal transplantation of stem cell–derived RPE have been under way for several years,^1-5 and the first-in-human transplantation of stem cell–derived photoreceptors are already being planned. It is hoped that within a few years, ophthalmologists will be able to offer vision-restoring therapies for patients with macular degeneration, inherited macular dystrophy, and other blinding conditions.

These developments are exciting and have been communicated widely in the popular press. As such, I am asked frequently by my own patients when analogous stem cell therapies might be available for the treatment of their glaucoma. Unfortunately, the issue of applying regenerative medicine to glaucoma is much more complicated. Optic neuropathies impair vision because of retinal ganglion cell (RGC) death. RGCs are central nervous system (CNS) neurons, which process and project visual information from the retina to multiple brain centers via their axons, which together compose the optic nerve. Although there are many reasons to be hopeful, restoring vision for patients suffering from optic neuropathies will require significantly greater scientific and clinical development than for patients suffering from macular degeneration or dystrophy. To equip vision care providers with the knowledge required to discuss this issue intelligently with their patients, this article will explore the current state of optic nerve regeneration science, the obstacles that the field must overcome, and salient points that should be communicated to patients who wonder about these possibilities.

Current State of the Science

The concept of therapeutic optic nerve regeneration has been considered for decades, since the discovery of species of fish and amphibians that naturally regenerate their retinas and optic nerves following injury.^6-8 However, several key developments in the past 15 years transitioned vision restoration for humans from science fiction to scientific possibility. The Nobel prize–winning discovery of induced pluripotent stem cells (iPSCs)^9,10 has enabled researchers to produce stem cells that have the ability to form any cell type in the adult human body directly from patient skin biopsies, blood samples, and even urine samples. Another Nobel prize–winning discovery, CRISPR-Cas9 gene editing,¹¹ now allows scientists to engineer the genome of these cells to correct inherited mutations in patient-derived iPSCs and to engineer cells with properties that make them traceable or more likely to survive or engraft into a recipient. Over the past 10 years, investigators have developed several robust methods to differentiate stem cells into RGCs,^12-14 which now offers a key tool that is needed to replace the RGCs that have been lost in patients with optic neuropathy. In fact, preclinical experimentation in RGC transplantation is accelerating. Key studies in the past several years suggest that RGCs transplanted into mice can survive and integrate into the retina.^15-19

Of course, getting repopulated RGCs into the recipient’s retina is only part of the challenge. Reconnecting the eye to the brain necessitates that those RGCs grow lengthy axons through the optic nerve and into the subcortical vision centers of the brain that are involved in visual perception. The mammalian central nervous system is notoriously resistant to regrowth of neuronal fibers, which is why spinal cord injury is such a difficult condition to treat. Like the spinal cord, the injured optic nerve resists RGC axon regrowth and contains repulsive cues including components of the myelin sheath and inhibitor signals such as a molecule called Nogo. Given these obstacles, the incredible strides that scientists have made in enabling RGC axon growth in recent years in noteworthy. Through genetic engineering of injured RGCs, visual stimulation, blockade of inhibitory signals, and combinations thereof, investigators have been successful in driving injured RGCs to regrow axons long distances within the optic nerve and sometimes even past the optic chiasm and into visual centers, including the lateral geniculate nucleus of the thalamus and the superior colliculus.^20-25

In short, scientific progress over the past 2 decades has provided the key tools needed to replace RGCs within the visual pathway for vision restoration. The key challenges to RGC replacement — making new RGCs from stem cells, transplanting them into the living eye, achieving long-term survival of grafted neurons, connecting donor RGCs to the recipient retina, growing RGC axons to the brain, and even myelinating those optic nerve fibers — have been successfully accomplished in isolation, albeit with low efficiency and in very specific experimental conditions. If these pieces of the puzzle can be put together into a comprehensive strategy to overcome all these challenges in series for a large number of newly derived neurons, then the ultimate goal of restoring vision for patients with advanced optic neuropathy might be attainable.

Obstacles to Clinical Translation

The complexity of RGC contributions to the visual system cannot be overstated. Unlike the 4 types of photoreceptors that directly receive visual input in the form of light and which each connect to a single bipolar cell, humans possess at least a dozen different RGC subtypes, which can connect to dozens of bipolar and amacrine cells in highly specialized retinal circuits and which project to dozens of brain targets in a highly organized manner that maintains the retinotopic map. Although stem cell biologists can make “generic” RGCs in a dish, recipes to create specific RGC subtypes have not yet been developed. Enabling RGCs to integrate into the retina, for instance by permeabilizing the internal limiting membrane,^26,27 puts the donor cells in the right place to make connections, but whether those connections will resemble the circuits that support higher level visual processing or how to control the patterns of retinal synaptogenesis remain unclear. Following transplantation, less than 1% of neurons transplanted into the eye survive for more than a couple of weeks, and so leveraging neuroprotection approaches to improving donor RGC survival will be critical. Also, although RGC axon regeneration can be stimulated, many regenerating fibers spontaneously grow into ectopic sites, crossing the chiasm and growing backwards into the contralateral optic nerve or meandering within the nerve tissue itself. Methods to guide axons to the correct location in the brain with high efficiency will be needed to efficiently restore eye-to-brain connections.

Patient Conversations on Vision Restoration

Clearly, monumental challenges persist, and many questions remain unanswered, making this a difficult topic to discuss with patients. When talking to patients, I like to describe the visual pathway as a telephone switchboard, the kind that were commonplace from the late 19^th to the mid 20^th century before direct dialing technology was developed. For us to see, a million (on average) cables connecting the eye to the brain need to be plugged in to the right locations on the switchboard. When glaucoma causes vision loss, hundreds of thousands of those cables become frayed and end up in the trash can. Until just a few years ago, we didn’t even have new cables to replace the broken ones, but now we do. The problem lies in plugging the new cables into the correct place on the switchboard. We have some techniques that can plug those cables into sockets on the board, but right now we can only do this for a small number of cables at a time. Moreover, we don’t really have control over which cables get plugged into which sockets. There is hope that if we can harness developmental signals to aid in rewiring (like referring to a map of the switchboard sockets), then enough cables could be replaced to rebuild the overall connection and restore some vision. However, developing these technologies will take time.

When patients ask how long will it be before stem cell therapy can help patients like them, unfortunately, it is impossible to say, but it is important to be realistic. Optic nerve regeneration is unlikely to be a subject of in-human clinical trial for several years at a minimum. It’s also important to understand the likely progression of capabilities for these theoretical therapies. Investigators will be delighted if RGC transplantation were able to restore light perception to patients with complete blindness, and such patients will likely be the first subjects of clinical trials. Restoring the ability to detect gradations of brightness, movement, and shapes adds a layer of complexity that will take significantly longer. Restoring vision to ambulatory levels will take even longer, and the ability to recognize faces or read will take even longer than that, if it is possible at all. However, it’s important that patients know there is reason to hope. Hundreds of passionate and dedicated scientists all over the globe are working hard on this problem, and helping patients like the ones sitting in your chairs is the driving motivation. For patients with congenital or juvenile-onset glaucoma, optic nerve regeneration therapies may begin clinical trials within their lifetimes.

A Cautionary Note

The gap between current scientific capabilities and what is needed to restore vision in optic neuropathy is sobering. While I hope I’ve convinced you that there is good reason to be hopeful for the future, it is critical that physicians and patients don’t let that hope trigger dubious decision making about ongoing treatment. Intraocular pressure reduction remains the mainstay of glaucoma therapy, and although neuroprotective treatments to help preserve vision are on the horizon, they are not yet widely available. Patients with end-stage disease and little or no vision can be desperate and sometimes willing to pursue unproven treatments hoping to regain visual function.

Over the years, multiple patients have asked me whether they should undergo stem cell therapy for their glaucoma. There are numerous “stem cell clinics” in the United States and abroad that offer stem cell transplantation to patients with glaucoma, as well as an array of other neurodegenerative diseases affecting the eye.²⁸ Some of these clinics claim to offer established treatments, and others purport to be conducting clinical research while charging patients large sums of money to be enrolled. For instance, in 2013 a patient shared with me information from a stem cell clinic that had registered its “study” at clinicaltrials.gov . They offered transplantation of bone marrow–derived mesenchymal stem cells for the treatment of several different retinal degenerative diseases and optic neuropathies and reported that past participants had experienced improvement in vision of “about 25% to 30%.” The cost of enrolling was between $19,600 and $20,600.

While the ethical and regulatory issues that surround this practice are unfortunately outside the scope of this editorial, I believe it is critical that ophthalmologists be aware of this and understand how to counsel patients accordingly. The risk to patients receiving unproven and unregulated stem cell transplants goes beyond the financial cost. Vision-threatening complications of intraocular stem cell transplants from “stem cell clinics” have been well documented in the literature and include ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, lens dislocation, and combined tractional and rhegmatogenous retinal detachment.^29-33 As such, patients need to understand that receiving untested stem cell treatments have the potential to leave them significantly worse off.

Well conducted human clinical trials are necessary for the advancement of science and medicine, and patients and doctors should be aware of some factors that will help in the decision of whether to participate in human subject research. First, clinical trials are governed by a set of rules that are designed to ensure the integrity of the research as well as the safety of the participants. They are overseen by an Institutional Review Board (IRB) which is independent of the investigators conducting the study. Patients interested in participating in a research study should inquire about the oversight structure of the trial, including the IRB that approved the study and any Data and Safety Monitoring Committee that might be involved. Second, registering a clinical trial on a national or international database (such as clinicaltrials.gov ) does not imply that adequate oversight is in place or that the trial is legitimate. Indeed, the clinicaltrials.gov website specifically states that “Listing a study does not mean it has been evaluated by the US Federal Government” and provides a useful page of information for patients to better understand clinical research (https://clinicaltrials.gov/ct2/about-studies/learn ). Lastly, it is uncommon (though not unheard of) that patients would be asked to pay for participation in a clinical trial. Clinical trials that require large sums of money from patients for enrollment should prompt extra scrutiny before participation is considered further.

Conclusions

Development of innovative treatments to restore vision in glaucoma and other optic neuropathies would be revolutionary for patients suffering from these diseases. Although regenerative medicine treatments for retinal diseases seem to be on the cusp of clinical translation, repopulating RGCs and regenerating the optic nerve is considerably more complicated than replacing RPE or photoreceptors and will require a much longer time horizon to reach our patients. Nonetheless, significant advancements in stem cell biology and neuroscience suggest that vision restoration for optic neuropathy may one day be feasible. In the meantime, it is critical that patients and their doctors balance hope for the future with a clear understanding of the most effective and clinically established methods of preserving the vision that they have now. GP

Thomas V. Johnson III, MD, PhD, is the Shelley and Allan Holt Rising Professor of Ophthalmology and an assistant professor of ophthalmology at Johns Hopkins Medicine in Baltimore, Maryland. He reports consultancy to AbbVie and research for Alcon, InjectSense, iCare USA, and Perfuse Therapeutics. Reach him at johnson@jhmi.edu.

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