Treating IRDs: Gene-Specific and Gene-Independent Approaches

A review of the different approaches to treating IRDs.

By Alessandro Iannaccone, MD, MS, FARVO

With more than 300 disease-causing genes mapped and more than 260 cloned,1 the field of inherited retinal diseases (IRDs) has experienced tremendous advances over the past 2 decades. This vast genetic heterogeneity represents both a great opportunity and a remarkable challenge.


• The development and delivery to bedside of gene/disease–specific treatments for each of the IRD-related genes identified to date is a daunting task that may take decades.

• Most gene therapy trials for IRDs rely on adeno-associated virus vector–based gene therapy and subretinal injection delivery.

• Efforts are underway to identify improved viral vectors that can achieve adequate, widespread transfection through the intravitreal route and to develop thin transvitreal cannulas that do not require vitrectomy.

The identification of the causes of so many forms of IRD and the growing body of knowledge of their functions and underlying disease mechanisms have allowed the development of exciting new gene/disease–specific treatment opportunities (Figure 1A). However, the development and delivery to bedside of gene/disease–specific treatments for each of the genes identified to date are daunting tasks that may require decades for full implementation.

With exciting new treatments now aimed at an even more granular level—targeting not just specific genes but, in fact, specific mutations—the task at hand is expanded by several orders of magnitude. Furthermore, gene/disease–specific treatments rely on persistent target cells and sufficient visual function to permit efficacy. For the many patients who are outside of this window of opportunity, other approaches are necessary. Thus, gene/disease–independent treatments (Figure 1B) are a top priority. This article reviews the state of IRD treatment approaches.

Figure 1. Researchers are exploring two pathways for treating IRDs—one that directly addresses underlying genetic dysfunction (A) and one that seeks to address the downstream effects of genetic mutation (B).


The field of gene augmentation therapy (gene therapy for short) witnessed a major breakthrough with the US FDA approval of voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) for RPE65-related retinopathies.2,3 Although this approval created major momentum in the field, this group of retinopathies is primarily of the Leber congenital amaurosis (LCA) and early-onset retinitis pigmentosa type, affecting a relatively small group of patients with IRDs. Thus, much work (and opportunity) is ahead in the field for additional gene therapies to be tested in human clinical trials and, one hopes, to become approved treatments for patients with IRDs. A list of such trials is provided in Table 1 in alphabetical order, and the list is growing rapidly.

It should be emphasized that, for gene therapy to be possible, knowledge of the causal gene for each disease and in each patient is necessary, underscoring the importance of genotyping affected patients via CLIA-certified diagnostic laboratories.

At this stage of the gene therapy era for IRDs, most trials rely on adeno-associated virus (AAV) vector–based gene therapy and a subretinal injection approach, as does voretigene. In most of the ongoing trials, the aim is to deliver a copy of the normal gene into photoreceptor or retinal pigment epithelium cells using the AAV vectors.

This invasive approach requires a full-fledged vitrectomy and retinotomy to deliver the treatment subretinally. A key limitation of this approach is that it is not possible to deliver gene therapy to the entire retina, but rather one or more areas must be chosen to receive the subretinal bleb that will define the treated area. Thus, the area or areas to be treated must also be chosen carefully, aiming for areas that display residual target cell integrity and, ideally, measurable function. For example, there may be little to no benefit in treating eyes with no measurable rod-mediated function if the gene to be delivered is a rod-specific one. Exceptions to this rule of thumb exist, however, and the RPE65-related retinopathies are a perfect example of this. In these conditions, there can be a significant mismatch between function and structural integrity.4

Other emerging strategies for gene therapy include the following:

Gene editing using CRISPR/Cas9–based technology, in which clustered regularly interspaced short palindromic repeats (CRISPR) complexed with a CRISPR-associated (Cas) nuclease can be used to create breaks in DNA sequences that can then be used to implement gene editing strategies.5,6 For example, a “cut and remove” strategy is being tested in the LCA-CEP290 Editas trial (Table 1).

Correction of the genetic defect downstream of the DNA sequence by targeting messenger RNA (mRNA) instead. In this approach, editing antisense oligonucleotides (eAONs) are used to correct the target defect after DNA transcription but before translation so that the resulting protein is normalized or greatly improved compared with the mutated version thereof. This strategy is being used in the ProQR trials (Table 1).7

At present, CRISPR/Cas9–based technology relies on the same AAV vector–based approaches as current gene therapies, whereas eAONs are small molecules that can be injected intravitreally. Thus, they can, at least in theory, reach any part of the retina capable of responding to therapy. Although the latter approach has inherent advantages—namely, its ease of administration and panretinal reach—the effects of the treatment diminish over time because incorrect mRNA continues to be produced by the mutated DNA of the patient. Therefore, repeated periodic injections are needed. Also, this technology is currently mutation- or exon-specific, meaning there is a need to develop multiple specific treatments for each gene to be able to treat all patients.

Nonetheless, there is now published evidence that eAON-based technology is delivering measurable benefits to LCA-CEP290 patients after a single injection.7 Another trial, for Usher syndrome type 2A, has begun, and more are planned for the relatively near future.

Disease-specific trials, unlike gene-specific trials, are aimed at tackling mechanisms or circumventing defects that are unique to a particular condition (Table 2). Examples of these include the recent trials in patients with RPE65- and LRAT-associated LCA using synthetic 9-cis-retinal8,9 and trials aimed at impeding vitamin A–mediated lipofuscin accumulation and toxicity in the retinal pigment epithelium of patients with Stargardt disease.


Nutritional antioxidant and neuroprotective approaches to IRDs have been tested with partial success over the past few decades,10-16 and some evidence-based promising ones are now being tested as well (Table 3).

Other approaches in this realm are mainly aimed at IRD patients with advanced disease for whom gene-specific treatments are no longer an option, or are visual restoration options for conditions in which the benefit of gene-specific approaches is limited to the remaining tissue but cannot be extended to other more affected areas (eg, macular atrophy in Stargardt disease). The only such method that is approved by the FDA is the Argus II retinal prosthesis (Second Sight).17,18

Ongoing experimental approaches include intravitreally injected or subretinally implanted stem cells and hybrid treatments that use an AAV vector–based approach to deliver to the inner retina artificial genes encoding for rhodopsin-like light-sensing visual pigments that are normally found only in light-sensitive microalgae.19,20 Thus, these approaches aim to bypass photoreceptor damage by conferring the ability to detect light to cells that normally have no (bipolar cells) or minimal (ganglion cells) light detection ability by themselves. Other similar approaches are under development.


Despite the legitimate excitement surrounding the field of IRDs and the tremendous momentum it is experiencing, there is a need to develop more effective and more easily administered treatments. The ongoing efforts to overcome the limitations of viral vector–based gene therapies, the further development of CRISPR/Cas9–based treatments, and higher throughput development of mRNA-targeting approaches promise to improve both the efficacy of gene therapy and the range of treatable diseases.

Options for treatment of genetic conditions caused by nonsense mutations are also being developed. These include subcutaneous delivery of advanced synthetic aminoglycosides optimized as translational read-through drugs, or TRIDs. In this category are the ELX compounds in development by Eloxx Pharmaceuticals. A similar mechanistic approach is used by Ataluren (PTC Therapeutics), an oral suspension drug being tested in other genetic diseases.

Major efforts are also underway to identify improved viral vectors that can achieve an adequate, widespread transfection rate through the intravitreal route and to develop alternative treatment delivery approaches, such as thin transvitreal cannulas that do not require a vitrectomy or suprachoroidal devices.

Likewise, growth in gene/disease–independent treatment options will afford an opportunity for more widely applicable therapies. One such example is the trial being planned by Sparing Vision, a French company that is working on launching trials with rod-derived cone viability factor, a thioredoxin-like antioxidant molecule that is normally produced by rods and that has protective and rescuing effects on cones.21 An approach such as this could prove invaluable for patients with primary rod diseases in whom too much rod damage has already occurred and in whom gene therapy aimed at restoring a normal protein expression in rods may no longer be a viable approach.

Other such gene-independent directions may include targeting the intracellular accumulation of toxic compounds and certain proinflammatory changes that occur in the retinas of patients with IRDs.22,23

Finally, as recently discussed at the ARVO 2019 meeting in Vancouver,24 drawing from the standards of care and clinical trials in oncology, the time for combination therapies for IRDs appears to be nearing. Trials in which gene/disease–specific approaches may be combined with nonspecific ones (eg, neuroprotective agents) can be envisioned in the near future.


Although many challenges remain for the treatment of IRDs, the field is experiencing tremendous momentum, and an increasing number of treatment options are becoming available. These treatments hold the potential to significantly improve the prognosis for patients affected by these otherwise progressive, visually debilitating, and at times blinding disorders.

1. RetNet Retinal Information Network. Accessed June 19, 2019.

2. 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;390:849-860.

3. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130:9-24.

4. Jacobson SG, Aleman TS, Cideciyan AV, et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: prerequisite for human gene therapy success. Proc Natl Acad Sci U S A. 2005;102:6177-6182.

5. Dalkara D, Goureau O, Marazova K, Sahel JA. Let there be light: gene and cell therapy for blindness. Hum Gene Ther. 2016;27:134-147.

6. Zheng A, Li Y, Tsang SH. Personalized therapeutic strategies for patients with retinitis pigmentosa. Expert Opin Biol Ther. 2015;15:391-402.

7. Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25:225-228.

8. Iannaccone A, Zarbin MA. A new era in medical therapy for retinal degenerative disease? Lancet. 2014;384(9953):1482-1484.

9. Koenekoop RK, Sui R, Sallum J, et al. Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial. Lancet. 2014;384:1513-1520.

10. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111:761-772.

11. Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol. 2011;128:403-411.

12. Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch Ophthalmol. 2004;122:1297-1305.

13. Berson EL, Rosner B, Sandberg MA, et al. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses. Arch Ophthalmol. 2004;122:1306-1314.

14. Hoffman DR, Hughbanks-Wheaton DK, Spencer R, et al. Docosahexaenoic acid slows visual field progression in X-linked retinitis pigmentosa: ancillary outcomes of the DHAX trial. Invest Ophthalmol Vis Sci. 2015;56:6646-6653.

15. Hughbanks-Wheaton DK, Birch DG, Fish GE, et al. Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial. Invest Ophthalmol Vis Sci. 2014;55:4958-4966.

16. Hoffman DR, Hughbanks-Wheaton DK, Pearson NS, et al. Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical trial. JAMA Ophthalmol. 2014;132:866-873.

17. da Cruz L, Dorn JD, Humayun MS, et al. Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology. 2016;123:2248-2254.

18. Ho AC, Humayun MS, Dorn JD, et al. Long-term results from an epiretinal prosthesis to restore sight to the blind. Ophthalmology. 2015;122:1547-1554.

19. Dalkara D, Duebel J, Sahel JA. Gene therapy for the eye focus on mutation-independent approaches. Curr Opin Neurol. 2015;28:51-60.

20. Baker CK, Flannery JG. Innovative optogenetic strategies for vision restoration. Front Cell Neurosci. 2018;12:316.

21. Sahel JA, Leveillard T. Maintaining cone function in rod-cone dystrophies. Adv Exp Med Biol. 2018;1074:499-509.

22. Lobanova ES, Finkelstein S, Li J, et al. Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration. Nat Commun. 2018;9:1738.

23. Iannaccone A, Radic MZ. Increased protein citrullination as a trigger for resident immune system activation, intraretinal inflammation, and promotion of anti-retinal autoimmunity: intersecting paths in retinal degenerations of potential therapeutic relevance. Avd Exp Med Biol. 2019 [in press].

24. Wheelock RM, Sieving PA, Aleman TS, et al. Special interest group (SIG) meeting: protection, correction, regeneration: are combination therapies in the future for inherited retinal degenerations? Paper presented at: Association for Research in Vision and Ophthalmology Annual Meeting; April 28, 2019; Vancouver, British Colombia.

Alessandro Iannaccone, MD, MS, FARVO
• Professor of Ophthalmology, Duke University School of Medicine, Durham, North Carolina
• Director, Duke Center for Retinal Degenerations and Ophthalmic Genetic Diseases and Duke Eye Center Visual Function Diagnostic Laboratory, Durham, North Carolina
• Financial disclosure: Consultant (Astellas Institute for Regenerative Medicine, ClearView Healthcare Partners, Editas Medicine, GLG Group, Guidepoint, Huron Consulting Group, Ionis Pharmaceuticals, IQVIA, Rhythm Pharmaceuticals, Roivant Pharma)


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Retina Today is a publication that delivers the latest research and clinical developments from areas such as medical retina, retinal surgery, vitreous, diabetes, retinal imaging, posterior segment oncology and ocular trauma. Each issue provides insight from well-respected specialists on cutting-edge therapies and surgical techniques that are currently in use and on the horizon.