Structural-Functional Correlates in Inherited Retinal Degenerations


The retina is made of several layers and structures with numerous functions that combine to detect light, giving animals sight. Genes work by encoding proteins to perform specific functions; within the retina and when a gene mutation is present, structures and functions of the retina degenerate. Luxturna is an FDA-approved medication developed to treat the RPE65 mutation via intraretinal injection by encasing genes in the shell of a virus that attaches to retinal cells. Genes are delivered to the cells after the virus breaks the cellular wall, enabling them to reproduce copies of healthy RPE65. There is currently no FDA-approved treatment for the RDH12 mutation but researchers are working on developing a drug similar to the Luxturna model. The current model for gene therapy treatment involves injecting medication into the retina above or below the fovea where the structure is most preserved. By altering where the drug is injected, with respect to retinal preservation, patients may experience a better visual outcome postoperatively.

While the retina is vast, only a small portion of it is responsible for our central vision; in gene therapy treatments, a drug is injected into said small area of the retina with the goal of introducing the missing gene into a patient so that he or she can mimic and produce their own copy of the gene. Currently, only a small amount of drug is being used, resulting in a small area of the retina that can generate the gene, improving vision. This results in an island of central vision surrounded by a doughnut of vision loss before the peripheral vision kicks in. Usage of retinal gene therapy drugs is relatively young in comparison to other medications and only small dosages in the central retinal are used to prevent possible adverse reactions. Patients who have had success with Luxturna treatments have regained certain aspects of their vision but only the exact area of the retina which had been treated is affected. By injecting gene therapy drugs into a wider area, with respect to the retinal structure, patients may expect to see less sea of darkness for status post-treatment.

Research pertaining to the retinal structural-functional correlates in its relation to gene therapy has not been extensively discussed in over fifteen years. Since then, the Food and Drug Administration has approved the first gene therapy drug and patients all over the world have received the vision-altering therapy; comparing their pre-operative testing and imaging to the that of their post-operative results has granted researchers a better look at what they have accomplished and hints to what improvements could be made for this and similar treatments.  By reviewing the past research on the impact of retinal structure on its function in those with and without hereditary retinal defects besides results gathered on patients’ status post retinal gene therapy treatment, we can see that altering the treatment protocol could prove beneficial.

The retina is the inner lining of the eye which contains light-sensitive photoreceptor cells that fuel the complex human visual (retinoid) cycle (Jacobson et al., 2017, p. 333). Photoreceptors respond to light through a chain of biochemical reactions and the brain transcribes the information from these cells into vision (Jacobson et al., 2017, p. 333). Temporal to the optic nerve lies the foveal pit. This central depression is surrounded by an area of increased thickness which thins out away from the parafoveal peak, less an area of thickening at the vertical poles of the optic nerve (Jacobson et al., 2017, p. 333). The thickness of the retina is the distance between the outermost inner limiting membrane and the retinal pigment epithelium (RPE); this is often measured via optical coherence tomography (OCT) scans by calculating the area between the vitreoretinal interface and RPE (Jacobson et al., 2017, p. 333).

 The area around the foveal has the highest rod density about three to five millimeters from the center, though the exact topography of rod receptors varies in from person to person (Jacobson et al., 2005, p.6181). This photoreceptor-rich ring is full of cone cells for daylight conditions and color vision as opposed to the remainder of the retina which houses the dark vision rod cells. Disruption of the retinoid cycle cause cone dystrophies, rod dystrophies, and cone-rod dystrophies (Behr, et al., 2003). Those with hereditary retinal dystrophies (HRD) caused by a gene mutation experience visual dysfunction have cone and/or rod dystrophies depending upon the mutant gene. The RPE65 gene encodes a specific protein in the RPE that is essential for vision but humans with a mutation of this gene (Jacobson et al., 2005, p.6181). RDH12 genes are similar in mechanism but encode a specific retinoid dehydrogenase (Aleman et al., 2018, p.5232).

Patients with RPE65 mutations have been found to have extremely reduced photoreceptor function and therefore suffer from visual loss early in life (Jacobson et al., 2005, p.6181). OCT imaging of subjects with an RPE65 gene defect show variation in topographical thickness resulting in no clear relationship of age to retinal thickness for this mutation (Jacobson et al., 2005, p.6181). Imaging also revealed that photoreceptor nuclear layer thicknesses are often higher than expected to be for certain amounts of visual loss in RPE65-mutants (Jacobson et al., 2005, p.6181). The dissociation of retinal structure to function in patients with RPE65 mutations leads to a defect in the visual cycle that is greater than the loss of photoreceptors (Jacobson et al., 2017, p. 334). In early-onset retinal degenerations caused by the RDH12 mutation, the structural-functional dissociation is different from other mutations including RPE65 (Jacobson et al., 2005, p.6181). For those with RDH12 (and PRPH2 or ABCA4) associated retinal defects, the preservation of the peripapillary retina is suggestive of light protection, resulting from the shadow from overlying retinal thickness (Aleman et al., 2018, p.5232).

Currently, there is no treatment for the RDH12 mutation but the FDA approved a gene therapy for RPE65 mutations (FDA, 2017). Luxturna (voretigene neparvove-rzyl) is a subretinal injection that delivers a normal copy of the RPE65 gene that retina cells can mimic and reproduce (FDA, 2017). Copies of the healthy the gene are spliced into defunct virus shells that attach to and penetrate retinal cells (Menon, 2018). The medication is injected into the retina where the most photoreceptor preservation had been observed – traditionally superior to the fovea to favor inferior field improvement — thus creating a reasonably sized bleb; within the first weeks, the eye begins replicating the non-mutant gene at the injection site (Scholle, 2018). The result is increased light and contrast- sensitivity, but many experience an increase in visual acuity in addition to the intended results (Menon, 2018).

This particular gene therapy is a one-time procedure with results that span a lifetime. While there are many benefits to this, it can be a drawback in certain respects – if treatment fails for any reason, the patient is not eligible to have the treatment again. Retinal cells can only begin producing healthy copies of RPE65 if they have been in direct contact with the medication under the injection bleb. Any area untouched by the bleb remains free of the new genetic copy and do not share the benefits of the treatment, leading to patches of sighted area in what could otherwise be a sea of darkness. While the Luxturna procedure is only possible for patients with remaining healthy retinal thickness, perhaps further research should explore the possibility of expanding the area of the retina that undergoes receives the injection.

While the placement of the drug is pivotal, the amount of injectable is equally important. For a drug that is best suited for children, miscalculation or errors in the formulation of medication can have dire consequences (Toney-Butler & Wilcox, 2019). To establish medication doses, researchers but strictly adhere to numerous regulations while conducting preclinical safety testing (Shen et al., 2018). Prior to human trials, researchers need to identify potential toxicity to organs following exposure while establishing the link from the drug to the organ, determine the effects of the drug to both the intended target and any unintended targets and identify how any of these effects would be relevant in human models, and establishing safety biomarkers clinicians can follow in human trials to standardize and monitor usage (Shen et al., 2018). Once figured, the maximum safe dose in animal models is then converted into a human equivalent before human trials begin; this dose is based less on pharmacologic activity as much as the minimal risk of toxicity level (Shen et al., 2018).

Additionally, it is well established that gene therapies for retinal degenerations suit patients better when they are younger and have more preserved retina. Those with both RPE65 or RDH12 mutations often experience irreversible vision loss between the ages of ten and twenty (Aleman et al., 2018, p.5232). gene therapy is most beneficial when the patient is younger and still has treatable retina – if the retinal is too degenerated, the treatment is ineffective, no matter the dose or strength (Aleman et al., 2018, p.5232). Cone and rod photoreceptor improvement is only obtainable if the cells still possess the ability to function.; if imaging and OCT reveal that rods and cones could potentially restore functionality from gene therapy intervention within the pericentral retina, treatment of the area(s) could provide visual improvement (Jacobson et al., 2005, p. 6182).  

Luxturna is manufactured in one dose strength and the procedure can only be performed once per eye. As the dose is fixed, the placement of the drug is the variable that can be further studied in animal models before performing human trials. Trials altering the location and area of the injectable falls under the same regulations as the initial animal trials for maximum dose safety (Shen et al., 2018). Pre-existing modes of standardization through imaging, OCT, pupillometry, microperimetry, and visual psychophysics in combination with full-field stimulus threshold testing and electroretinography in conjunction with one another not only monitor the efficacy of the treatment location but the safety of the patient (or animal) being treated (Aleman et al., 2018, p.5232).

Dr. Albert Maguire, one of the pioneers of the Luxturna treatments, explains that varying the location of the injection – and even having a patient undergo a second gene therapy procedure – is physically possible and that recipients could have visual improvement in addition to experienced status post the preceding procedure. Multiple injections of Luxturna in bilateral poles have been performed with success in animal models but the hurdle to jump is that of drug approval. Luxturna is the most expensive medication in history with bilateral injections costing $850,000 (Berkrot, 2018). Though it is possible to study the drug in animal or human subjects while remaining well within the regulations for safety and efficacy, experimentation is not financially plausible at this time. Researchers working with Luxturna may find an increase in visual success in human patients through further research, as insurance would deny payment of the drug a second time and, while there is no gene therapy option for those with RDH12 mutations, pursuing treatment of multiple areas within the pericentral retina before reaching the market could prove to be a worthy trial strategy.

Retinal genetic mutations are not identical. Different mutations affect different cells and structures within the retina and cannot be treated as the same. A therapy model that has proven successful for RPE65 may not yield the same results for RDH12-mutant patients. Anatomy and photoreceptor preservation vary from case to case and it is imperative to treat each patient and mutation-specific to their condition. The Luxturna medication can only treat the RPE65 mutation but a similar drug delivery system for other genes could potentially work with respect to the retinal preservation.

A single injection site encompassing one pole of the retina has been successful but exploring the retina further for additional treatable areas could improve vision in gene therapy patients further. Preserved cells and retinal structures outside of the single established treatment region are indeed treatable and should be respected as such. Luxturna is past its trial stages and has been approved by the FDA but emerging gene therapies that target the retina have not been; through animal trials, if a positive link between treating various areas and improved visual outcome can be established, similar tests can be performed during human trials. If studies reveal a positive outcome, perhaps further exploration of the placement of Luxturna can be performed. The financial cost of Luxturna prevents it from being given multiple times to the same eye but this should not be a reason for patients not to receive the best care and improvement possible. Until every worthwhile treatable area has been tested and treated, the care of patients with HRDs is lacking.


Aleman, T. S., Uyhazi, K. E., Serrano, L. W., Vasireddy, V., Bowman, S. J., Ammar, M. J., . . . Bennett, J. (2018). RDH12 mutations cause a severe retinal degeneration with relatively spared rod function. Investigative Ophthalmology & Visual Science, 59(12), 5225-5236. DOI:10.1167/iovs.18-24708 [doi]

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Jacobson, S. G., Cideciyan, A. V., Aleman, T. S., Sumaroka, A., Schwartz, S. B., Windsor, E. A., . . . Thompson, D. A. (2007). RDH12 and RPE65, visual cycle genes causing Leber congenital amaurosis, differ in disease expression. Investigative Ophthalmology & Visual Science, 48(1), 332-338. DOI:48/1/332 [pii]

Menon, P. (Host). (2018, June 12). Reversing blindness with new FDA approved retinal gene therapy. [Audio Podcast Episode]. CureTalk. Retrieved from event/rsvp/Reversing-Blindness-with-New-FDA-Approved-Retinal-Gene-Therapy/305/

Shen, J., Swift, B., Mamelok, R., Pine, S., Sinclair, J. & Attar, M. (2018). Design and conduct considerations for first-in-human trials. Clinical and Translational Science, 12(1), 6-19.

Scholle, T. (2018, November 28). Subretinal injection of Luxturna. American Academy of Ophthalmology. Retrieved from

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