Gene Therapy Implications for Retina Specialists

Evolving endpoints, novel orphan disease treatment paradigms, and the dawn of precision medicine.


The 2017 US Food and Drug Administration (FDA) approval of the first gene therapy for a genetic disease begins what many hope to be a new cycle of innovation in retinal therapies.1 However, it also introduces novel and potentially challenging paradigms to the retina specialist, including unfamiliar functional vision endpoints, new orphan disease treatment pathways, and precision medicine and genetic testing requirements.

The retina community can adapt to these new paradigms to prepare for anticipated further innovation. The retina is a prime target for gene therapy research, given the large number of monogenic disorders, accessibility to target cell delivery, the ability to monitor noninvasively for disease progression or therapeutic response, and relative immune privilege that limits inflammatory response.2-4 This article will review these paradigms and their implications for retina specialists as they prepare for the future.


The retina community has historically relied on visual acuity as the key measure of visual function. For example, the proportion of subjects losing less than 15 letters of best-corrected visual acuity (BCVA) has been used as a primary endpoint in phase 3 registration trials of anti-VEGF agents for neovascular age-related macular degeneration, as in the MARINA and ANCHOR ranibizumab trials, as well as the VIEW aflibercept trials.5-7 However, BCVA may only be affected late in the course of retinal disease, as is the case with inherited retinal dystrophies (IRDs) that primarily affect rods and peripheral vison. Furthermore, both patients and the FDA are interested in functional vision, or a person’s ability to use vision in activities of daily living, such as reading or navigating. Novel functional vision endpoints will become more important in the coming decade as gene therapies for IRDs undergo clinical trials and potential commercialization.

For example, the efficacy of Luxturna (Spark Therapeutics) was established on the basis of a novel assessment of functional vision, the bilateral multiluminance mobility test (MLMT).8 The MLMT was developed in response to the need for a relevant, reliable, and clinically meaningful measure of functional vision in patients who were participating in clinical trials.9 It was developed, incorporating feedback from the FDA, to measure ambulatory vision at real-world light levels encountered during activities of daily living, and it underwent its own rigorous validation study.9,10 This mobility course, with 12 standardized configurations having the same number of turns and obstacles, was designed to be navigable by children as young as age 3.10

In the Luxturna clinical trials, the MLMT was assessed using both eyes and each eye separately at 1 or more of 7 levels of illumination, ranging from 400 lux (corresponding to a brightly lit office) to 1 lux (corresponding to a moonless summer night).8 The MLMT of each subject was videotaped and assessed by independent graders, and the score was determined by the lowest light level at which the subject was able to pass the MLMT.9,10 The MLMT change score was defined as the difference between the score at baseline and the score at 1 year.10 A positive MLMT score change from baseline to 1 year indicated that the subject was able to pass the MLMT at a lower light level.9 An MLMT score change of 2 or greater is considered a clinically meaningful benefit in functional vision.8 Tests of functional vision such as the MLMT will become more common in clinical trials of retinal therapeutics, so it is important for the retina specialist to understand these new efficacy paradigms.


The retina community has generally not been exposed to treatments approved for orphan diseases, and an understanding of orphan disease treatment pathways is helpful as gene therapies for IRDs undergo clinical trials and potential commercialization. Historically, rare diseases have been neglected, or “orphaned,” in drug development due in part to the inherent challenges of lengthy and expensive clinical trial operations in small, often geographically dispersed patient populations. These small patient populations complicate clinical study, not only through limited study recruitment, but also through limited natural history data. These issues impacted the development of Luxturna for the treatment of biallelic RPE65 mutation-associated retinal dystrophy, which necessitated separate studies of natural history, while requiring nearly a decade for phase 1-3 study recruitment and assessment of primary endpoints.11,12

Furthermore, even with successful approval, commercialization potential is limited in small markets, like IRDs. In recognition of these unique challenges and the unmet needs of patients with rare disorders, the FDA and European Medicines Agency (EMA) have incentivized development of therapies for these conditions. In the United States, the Orphan Drug Act of 1983 provided developers of treatments for orphan diseases — defined currently as those diseases that affect fewer than 200,000 Americans13 — with protocol assistance, tax credits to defray the cost of development, a waiver of FDA fees, and 7 years of market exclusivity.14 The orphan disease definition may also include diseases affecting more than 200,000 when costs associated with developing and marketing the therapy are not expected to be recovered after commercialization. The EMA provided similar incentives in 2000, with orphan designation for products addressing life-threatening or debilitating disorders affecting 5 or fewer per 10,000 individuals.15

Although the US Orphan Drug Act of 1983 partially addressed some of the challenges surrounding the development of therapeutics for rare diseases, the business model surrounding the development of gene therapies is even more complex and unique. While the current health care system may readily value chronically administered medications, it may not properly value therapies that deliver long-lasting benefits in one dose or one administration. Consequently, new reimbursement models are necessary, and there has already been some public discussion of health coverage approaches that consider installment payments and/or tie payment to real-world treatment effectiveness.

In addition, treatments for orphan diseases often involve unique care pathways because the rarity of the disease often necessitates centralization of care with multiple providers. In particular, centralized care facilitates safety and treatment optimization because consistent patient and procedural volume drives a cycle of expertise, positive outcomes, and continued referrals. In some cases, health authorities can mandate a centralized treatment center model as part of a risk-management plan to maximize patient safety. Complex quaternary referral patterns result, with only a few treating specialists at multidisciplinary centers, but difficulties with navigating a complex process or finding a treatment center may restrict access for some patients. In retina care, these referral patterns already exist to some extent for patients seeking treatment for choroidal melanoma or retinal detachment from retinopathy of prematurity. Centralization of care will likely exist, at least initially, for IRD gene therapy.


The dawn of precision medicine has far-reaching implications for retina specialists. Prior to the advances in molecular genetics, patients with IRDs generally received clinical diagnoses, and genetic testing was not commonly performed. However, more than 260 genes are known to cause IRDs,16 and if retina specialists wish to remain current, genetic testing must be adopted in clinical practice. Genetic testing is recommended for most patients by the American Academy of Ophthalmology when clinical findings indicate retinal dystrophy that is possibly associated with genetic mutations.17 Genetic testing can confirm suspicion of an IRD; provide an accurate diagnosis and information about prognosis and management; and assist in counseling of families, including family member risk assessment.18 In a study of 48 patients clinically diagnosed with RP, 87% desired genetic testing.19 With advancement in gene therapy, identifying a specific genetic mutation may help people with an IRD and their family members find clinical trial opportunities. Today more than 100 recruiting, enrolling, or active clinical studies for IRDs are listed on .

Unfortunately, ordering and interpretation of genetic test results is complex, but facility with the basics of interpretation is useful (Figures 1 and 2). While single-gene testing is inexpensive, it requires a working clinical diagnosis, and consequently it has limited utility in many cases, given the nonspecific nature of clinical findings in many IRDs.19 Gene panels are more commonly used, and generally focused on diagnoses associated with multiple genes.19 Whole genome/exome sequencing is the most comprehensive, but it generates a high number of variants of uncertain significance (VUSs).19 Genetic testing results are not binary, and they involve a ranking system of each identified mutation based on standards released by American College of Medical Genetics and Genomics (pathogenic, likely pathogenic, VUS, likely benign, benign).20

Figure 1. Genetic testing information vs cost.19

Figure 2. Genetic test interpretation, a ranked system from the American College of Medical Genetics and Genomics.20

Pathogenicity is determined by multiple factors, including the effect on gene coding, protein structure/function, variant association with disease in the population and in vitro/in vivo functional studies.20 Variants of uncertain significance can be especially difficult to address. A VUS involves a mutation variant for which there is a lack of affirmative data of pathogenicity or nonpathogenicity. A VUS may be reclassified in the future, as more information accumulates. Genetic counselors can certainly assist patients in selecting genetic tests, interpretation of genetic test results, and family planning. However, working with genetic counselors also introduces a new relationship to care coordination for the retina specialist. Fortunately, their services can be covered by insurance, and some providers are available for patients via a telemedicine interaction.

Finally, although detailed review is beyond the scope of this article, retina specialists need to be familiar with the major categories of gene therapy, including gene augmentation (adding a gene to a cell), gene editing (revising the existing genetic code), gene inactivation (silencing a gene, often a dominant negative one), and selective toxicity (as in chimeric antigen receptor or CAR-T cells to recognize cancer cells).


With the potential for continued rapid therapeutic innovation in gene therapy, retina as a specialty has an exciting future. To remain current, retina specialists must understand novel paradigms. These include unfamiliar functional vision endpoints, new orphan disease treatment pathways, precision medicine, and genetic testing requirements. RP


  1. Luxturna (voretigene neparvovec-rzyl) December 19, 2017 approval letter. Silver Spring, MD: US Food & Drug Administration;2017. Available at .
  2. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3(11):879-889.
  3. Takahashi VKL, Takiuti JT, Jauregui R, Tsang SH. Gene therapy in inherited retinal degenerative diseases, a review. Ophthalmic Genet. 2018;39(5):560-568.
  4. Boye SE, Boye SL, Lewin AS, Hauswirth WW. A comprehensive review of retinal gene therapy. Mol Ther. 2013;21(3):509-519.
  5. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
  6. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
  7. Heier JS, Brown DM, Chong V, et al ; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548.
  8. Luxturna (voretigene neparvovec-rzyl) US full prescribing information. Philadelphia, PA: Spark Therapeutics, Inc.;2017. Available at .
  9. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.
  10. Chung DC, McCague S, Yu ZF, et al. Novel mobility test to assess functional vision in patients with inherited retinal dystrophies. Clin Exp Ophthalmol. 2018;46(3):247-259.
  11. Chung DC, Bertelsen M, Lorenz B, et al. The natural history of inherited retinal dystrophy due to biallelic mutations in the RPE65 gene. Am J Ophthalmol. 2018. [Epub ahead of print]
  12. Spark therapeutics announces positive top-line results from pivotal phase 3 trial of SPK-RPE65 for genetic blinding conditions [press release]. Philadelphia, PA: Spark Therapeutics, Inc., October 5, 2015. Available at
  13. Orphan products: hope for people with rare diseases. Last updated March 1, 2018. Available at .
  14. Orphan Drug Act. In:1983:21 U.S.C., Ch. 29, Subch. V, Part B, §§ 360aa-360ff361, as amended.
  15. Regulation (EC) No 141/2000 of the European parliament and of the council of 16 December 1999 on orphan medicinal products. Official J European Communities. 2000;22(1):L18/11-15.
  16. Daiger SP. RetNet: summaries of genes and loci causing retinal diseases. Available at . Last updated January 4, 2019.
  17. Duncan JL, Bernstein PS, Birch DG, et al. Recommendations on clinical assessment of patients with inherited retinal degenerations - 2016. Available at .
  18. Retina International. Role of genetic tests in IRDs and RED. Available at
  19. Lee K, Garg S. Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies. Genet Med. 2015;17(4):245-252.
  20. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.