Restoring the Retina: Coming Advancements to Repair Structure and Function

Implantation under general anesthesia of a retinal prosthesis Argus? II (Second Sight), Ophthalmology department of Bordeaux Hospital, France.
With new technologies and techniques, research is offering new ways to revive vision loss from retinal damage and disease.

The ophthalmic literature is replete with studies that open with frightening statistics on the rapid expansion of retinal diseases. Researchers frequently identify age-related macular degeneration (AMD) as the leading cause of blindness in the United States. It’s also common to see them point out that both AMD and diabetic retinopathy, another retinal disease topping that list, are nearing epidemic levels, with AMD numbers expected to double in the next 30 years. And while these are the most prevalent, a number of other retinal diseases threaten vision and have few treatment options. How can ophthalmologists, using the tools they have, possibly combat such gargantuan foes — ones primed to steal the vision of more than 20 million Americans by 2050?1

If necessity is the mother of invention, the expected rise in retinal disease is expecting quite the litter. In addition to anti-vascular endothelial growth factor drugs that can slow (and in some cases reverse) vision loss, advances in technology, such as gene therapy, retinal and cortical implants, and autologous retinal transplantations, are offering innovative ways to revive retinal functioning that, less than a decade ago, may have been irretrievable.2 

In recognition of Low Vision and AMD Awareness Month, this article reviews these latest additions to the ophthalmologist’s armamentarium and offers hope to patients on the cusp of vision loss.3

Retinal Gene Therapies

Some cases of retinal degeneration are associated with gene mutations. While cells that are nonfunctional or have died in the retina can only be replaced through stem cell transplantation, gene therapies can target the remaining viable cells to prevent them from becoming unhealthy and degenerating, explains Jesse Sengillo, MD, an ophthalmologist at Bascom Palmer Eye Institute of the University of Miami Health Systems.

“The regular, or normal, copy of the gene is packaged into a vector, and the vector is delivered to the subretinal space in most cases,” Dr. Sengillo says. “There, it finds the target cells of the retina and provides the normal copy of DNA into the cells so that those cells regain function.”

The adeno-associated virus vector-based gene therapy voretigene neparvovec, which treats retinal dystrophy caused by a mutation in the RPE65 gene, is currently the only FDA-approved gene therapy for an inherited retinal disease. Clinicians who suspect this particular indication can perform genetic testing to see whether the patient is a candidate for the treatment. Patients can expect, based on results from clinical trials, possible improvement in functional mobility, Dr. Sengillo says. Currently, the treatment is only available in select centers in the United States.

Dr. Sengillo adds that several other gene therapies are currently under development. They include treatments for choroideremia, X-linked juvenile retinoschisis, Usher syndrome type 1 and 2, and mer tyrosine kinase (MerTK)-associated retinal dystrophy. 

Ophthalmologists can direct patients with these dystrophies to tertiary care centers or experts who conduct genetic testing to determine the genetic defect and direct them toward relevant clinical trials or the RPE65 treatment.

Although in its infancy, CRISPR, a newer biological technology that edits mistakes in DNA, may provide a promising approach to autosomal dominant conditions of the retina, Dr. Sengillo explains.

Stephen Tsang, MD, PhD, an ophthalmologist at the Edward S. Harkness Eye Institute at Columbia University, and his team have reviewed therapies for rhodopsin-mediated autosomal dominant retinitis (RHO-adRP), a hereditary degenerative disorder with several clinical phenotypes caused by more than 150 mutations in the RHO gene that causes retinitis pigmentosa.4

A pair of clinical trials using optogenetics as non-targeted gene therapy in retinitis pigmentosa patients are presently underway: RST-001 (NCT02556736) and the PIONEER study (NCT03326336).

There are also targeted gene therapies for RHO-mediated adRP that strive to inhibit mutant RHO gene expression and increase the ratio of wild-type (WT)-to-mutant RHO to slow retinal degeneration, either through mutation-specific or mutation-independent gene therapy strategies.

PR1123, an antisense oligonucleotide drug, specifically targets the P23H mutation in the RHO gene. IC-100, which is mutation-independent, is a gene therapy product developed from 1 AAV2/5 vector expressing an shRNA targeting RHO and a healthy copy of the RHO gene that resists the shRNA. Both have phase 1/2 studies underway.

Dr. Tsang’s team has also explored the potential of TGFβ, a major anti-neuroinflammatory cytokine, in treating retinitis pigmentosa. According to their research, TGF- β1 coding adeno-associated virus serotype 8 promoted cone survival in retinitis pigmentosa Pde6b and Rho models involving mice.5

Retinal and Cortical Implants

Another technology-in-the-works, retinal implants, replace the damaged tissue with an implantable device. Specifically, the implant replaces photoreceptors in either inherited disease, such as in retinitis pigmentosa, or disease of acquired degeneration, such as AMD. Retinal implants capture light and stimulate secondary neurons that have remained in the retina, such as ganglion cells and bipolar cells, which then send signals to the brain through the optic nerve.

“Patients who get a retinal implant will see at least flashes of light,” says Gislin Dagnelie, PhD, associate professor of ophthalmology at Johns Hopkins University School of Medicine and the associate director of the Lions Vision Research and Rehabilitation Center at the Wilmer Eye Institute. “How much more they will see really depends on the technology and the state of the retina.”

Retinal implants can be placed on top of the retina, which is the easier option to accomplish surgically, but the curvature of the implant may not precisely match the curve of the patient’s retina and it needs to be held in place, which is often accomplished via a retinal tack, which holds it onto the sclera. Alternatively, the implant can be placed under the retina, which presents other challenges.

Dr. Dagnelie explains the retina’s bipolar cells reorganize in the absence of photoreceptors by forming cross-connections that would not normally exist, presenting visual complications for the patients who receive retinal implants.

In diseases where no working connection between the eye and the brain remain, such as end-stage glaucoma or trauma of the optic nerve, the implant must be placed in the brain to attempt to restore vision, he says. 

“The advantage of that is that you get much closer to the target cells, and you can probably get much more detailed information, but we really don’t know yet how well that will work,” Dr. Dagnelie says.

Researchers in Amsterdam implanted a 1024-channel prosthesis in areas V1 and V4 of the visual cortex of monkeys and used electrical stimulation to both elicit phosphenes on electrodes and impose patterns of phosphenes.6 The monkeys were able to recognize them as shapes, motions, or letters.

In Chicago, researchers are planning to surgically implant The Intracortical Visual Prosthesis System at Rush University Medical Center in volunteers who are blind.7 The experiment will test whether implanted wireless stimulators can enable the participants to see rendered images.

“The way that system works is that there are little modules of 4×4 electrodes, and each of the modules has its own wireless connection to the outside world,” Dr. Dagnelie says. “You can take a whole bunch of these and punch them into the visual cortex and try to create an image by stimulating enough of these electrodes. What we’ll probably see is that the first of these patients that they’re going to be implanting soon will have about 10 of these little modules, so about 160 electrodes. And hopefully, the ones after that will have more. If it all works, and if the patients indeed see dots of light and they can make images of those dots of light, we’ll see what level of vision these patients get.”

Cortical implants carry typical surgical risks and researchers believe that, once the implants are in place, the risks are relatively minor, he says.

“Right now, there really isn’t anything that will give a blind person good vision, but there is hope that either the retinal or cortical implant, with more research, will lead to an implant that will give them some level of useful vision — at least enough to orient themselves,” Dr. Dagnelie says.

Autologous Retinal Transplantation

Researchers are also refining the surgical technique of autologous retinal transplantation (ART), which can address macular holes. A study in Ophthalmology evaluated 33 surgeons from around the world who employed the technique to repair primary macular hole, a refractory macular hole, or combined macular hole-rhegmatogenous retinal detachments (MH-RRDs) for the ART Global Consortium.8

This technique employs an autologous neurosensory retinal free flap that is harvested and moved over the hole. This study evaluated 130 eyes from 130 patients who also underwent pars plana vitrectomy.

The report shows that intraoperative complications were “rare.” Among the 35 surgeries for primary macular holes, 86% closed after surgery, and 88% of the 76 ART surgeries for refractory macular holes closed. In the MH-RRD surgeries, 95% of the macular holes closed.

Ultimately, the study shows ART led to anatomic and functional improvements in patients with both primary and refractory macular holes, as well as combined MH-RRDs. 

“These results suggest that a vitreoretinal surgeon may consider grafting techniques for large, primary macular holes or if a macular hole failed to close by traction-relieving techniques, such as vitrectomy, ILM peeling, or ILM flaps with gas tamponade,” the report shows. “In this study, 25% of patients with refractory macular holes (all of whom had undergone ILM peeling previously) gained 5 lines or more of VA. Thus, patients have a meaningful opportunity for a better functional outcome if ART or grafting surgery is performed, as evidenced by the visual gains in the refractory MH group.”

A later study adds to this, showing that 6 out of 13 patients who underwent ART procedures had a closed macular hole at the end of the follow-up and complete recovery of the myoid/ellipsoid layer. The remaining showed a 44.9% reduction of the initial gap. However, although that study demonstrated a positive trend toward visual recovery (P =.034), after the correction of the alpha value, the change lost its statistical significance. During follow-up, 1 patient did develop a mild proliferative vitreoretinopathy and epiretinal membrane without anatomical or functional consequences.9

A Tangible Influence

Ophthalmology is far from the only medical discipline turning to technology to restore function. Bionic devices are becoming more commonplace throughout health research as monitoring devices keep patients with diabetes in check, improved cochlear implants are giving new options to those with hearing loss, and researchers are developing brain implants to help some patients with paralysis move. As important as those systems are, we know that vision impairment, even when it is not severe, is associated with significant, “tangible influence” on quality of life.10 By making room for these new concepts, ophthalmology has the potential to restore function and revive not just vision, but the human experience itself.


1. Pennington K, DeAngelis M. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016;3(12):34. doi:10.1186/s40662-016-0063-5.

2. Wykoff C, Eichenbaum D, Roth D, Hill L, Fung AE, Haskova Z. Ranibizumab induces regression of diabetic retinopathy in most patients at high risk of progression to proliferative diabetic retinopathy. Ophthalmol Retina. 2018;2(10):997-1009. doi:10.1016/j.oret.2018.06.005.

3. February is low vision awareness month. Center For Sight. Published online February 18, 2020.

4. Meng D, Ragi SD, Tsang SH. Therapy in Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa. Molecular Therapy. 2020;28(10):1-11. doi: 10.1016/j.ymthe.2020.08.012

5. Caruso S, Ryu J, Quinn PMJ, Tsang SH. Precision metabolome reprogramming for imprecision therapeutics in retinitis pigmentosa. J Clin Invest. 2020;130(8):3971–3973. doi: 10.1172/JCI139239.

6. Chen X, Wang F, Fernandez E, Roelfsema PR. Shape perception via a high-channel-count neuroprosthesis in monkey visual cortex. Science. 2020;370(6521):1191-1196. doi: 10.1126/science.abd7435

7. Ceron-Reyes M. $2.5 million award will move first-of-its-kind visual prosthesis brain implant to a clinical trial. Illinois Institute of Technology. Published online September 1, 2020.

8. Moysidis SN, Koulisis N, Adrean SD, et al. Autologous retinal transplantation for primary and refractory macular holes and macular hole retinal detachments. Ophthalmol. Published online October 9, 2020. doi: 10.1016/j.ophtha.2020.10.007

9. Rojas-Juárez S, Cisneros-Cortés J, Ramirez-Estudillo A, Velez-Montoya R. Autologous full-thickness retinal transplant for refractory large macular holes. Int J Ret Vit. Published online November 23, 2020. doi:10.1186/s40942-020-00266-5 

10. Cumberland P, Rahi J, for the UK Biobank Eye and Vision Consortium. Visual function, social position, and health and life chances. JAMA Ophthalmol. 2016;134(9):959-966. doi:10.1001/jamaophthalmol.2016.1778