Emerging Treatments for Inherited Retinal Degenerations

Targeted therapy goes viral and beyond.


Emerging Treatments for Inherited Retinal Degenerations

Targeted therapy goes viral and beyond.


Inherited retinal degenerations (IRD) are rare genetic disorders of the retina and/or choroid with a broad spectrum of symptoms, inheritance patterns, ages of onset, rates of progression, and phenotypic characteristics.

For example, even the most common IRD, retinitis pigmentosa (RP), with a worldwide prevalence of 1:4,000,1 is associated with all inheritance patterns, an age of presentation that spans from the first year to the sixth decade of life, and variable severity of progression that can lead to legal blindness over the course of years to many decades.

The combination of relatively low prevalence, high variability of presentation, and necessity of specialized visual diagnostic equipment makes the diagnosis of IRD inherently challenging. However, now more than ever, accurate diagnosis of IRD can have a tremendous impact on the way patients and families are counseled, not only for family planning and diagnosis of affected relatives, but also with regard to the options for participation in the multitude of emerging clinical trials for the treatment of IRD. As such, the scope of this article will not be a comprehensive review, but rather will be limited to the discussion of IRD for which there are currently active treatment trials in the United States.

At tertiary referral centers for IRD, widefield multimodal imaging, spectral domain optical coherence tomography, 90° full-field perimetry, and electroretinography (ERG) are used to complement the ocular exam, history, and pedigree, all of which guide the ordering and interpretation of confirmatory genetic testing and segregation analysis.

Although there are currently more than 250 genes known to be associated with IRD, the list is far from complete. Thus, the genetic testing detection rate has been estimated to be ~50% to 60%,2-4 underscoring the value of clinical suspicion and need for high pretest probability.

Cristy A. Ku, MD, PhD, is a postdoctoral fellow at Casey Eye Institute of the Oregon Health & Science University (OHSU) in Portland. Paul Yang, MD, PhD, serves on the faculty of Casey Eye Institute of OHSU. Rachel C. Patel, BA, at the University of Massachusetts Medical School in Worcester. None of the authors reports any financial interests in products mentioned in this article. Dr. Yang can be reached via e-mail at

While the precision, speed, and cost of genetic sequencing have advanced greatly in past years with the advent of next-generation sequencing and high-throughput strategies, a firm clinical diagnosis is still crucial to the interpretation of the not uncommon scenario of an inconclusive result, due to variations of unknown significance in the gene(s) in question.

That said, there must be a high degree of confidence in both the clinical diagnosis and confirmatory genetic test results for a patient to be eligible for most targeted therapies under clinical trials.


Although there is still no proven cure, rapidly emerging developments in the clinical management and therapy for IRD provide hope for the potential of vision preservation and even functional restoration for these devastating diseases.

The therapeutic options can be broadly categorized into three strategies: (1) slowing retinal degeneration via neuroprotection; (2) stopping disease progression by treating the genetic mutation; and (3) reviving visual function by the replacement of lost tissue or the substitution of photoreceptor function.

Most of the original clinical treatment studies in IRD have investigated the effects of oral nutritional supplementation in large heterogeneous groups of patients with RP. Novel approaches to therapy in IRD have begun targeting biochemical pathways specific to the genetic mutation and disease pathophysiology. In particular, gene and cell-based therapies have received much attention because these two platforms for delivering therapy are relevant across all three treatment strategies (Figure).

Figure. Gene and cell-based therapies currently in clinical trials in the United States.

The eye is particularly suitable for the delivery of gene and stem cell therapy because the ocular globe is anatomically distinct, readily accessible, and possesses some degree of immune privilege. The emergence of these targeted therapies offers hope for patients with IRD but also underscores the need for accurate diagnosis and genetic confirmation testing.


Slowing disease progression via retinal neuroprotection is mainly based on oral medications and nutritional supplements that are thought to improve the retinoid visual cycle, act as antioxidants, and/or mediate cell death. Cell-based approaches to neuroprotection are being developed to deliver neurotrophic factors that may also have antioxidant properties and promote photoreceptor survival.

Retinoids play a central role in the visual cycle and are obtained from dietary vitamin A as retinol and retinyl esters in meat and dairy or carotenoids in fruits and vegetables.5 The initiation of phototransduction involves the activation of the essential vitamin A-derived chromophore, 11-cis retinal, which must then be regenerated via the retinoid cycle, a series of enzymatic reactions within the photoreceptor outer segments (OS) and retinal pigment epithelium (RPE). Thus, a deficiency of 11-cis retinal due to a lack of dietary vitamin A or genetic mutation affecting the retinoid cycle can cause visual dysfunction and retinal degeneration.5

Most notably, mutations in RPE65- or LRAT- cause deficiencies in 11-cis retinal and are associated with Leber congenital amaurosis (LCA), the most severe early-infantile form of RP. A stable synthetic form of 11-cis-retinal called QLT091001, a 9-cis-retinal analog, has been shown in phase 1b clinical trials to improve visual acuity and visual fields in patients with RPE65- or LRAT-associated LCA.6 The benefits of repeated oral administration of QLT091001 are currently being examined (NCT01521793).

Moreover, genetic mutations in the retinoid cycle can also cause a buildup of retinoid metabolites that leads to cellular damage through the generation of reactive oxygen species and toxic metabolites.

In particular, mutations in the ABCA4 gene associated with Stargardt dystrophy7 and RP8,9 lead to an accumulation of all-trans-retinal and subsequent irreversible formation of the toxic retinoid dimer, N-retinyl-N-retinylidene ethanolamine (A2E), in OS disc membranes.10 Thus, while a proper supply of retinoid precursors is essential for maintaining the visual cycle, an abnormal accumulation of retinoid metabolites can be cytotoxic.

Consequently, caution must be exercised with the prescription of vitamin A in patients with RP, especially those who have not yet been genotyped. High-dose vitamin A palmitate supplementation has been shown to slow the decline of cone photoreceptor function on ERG, but had no significant effect on visual field or visual acuity in patients with RP.11

As such, the practice remains controversial due to opposing opinions12 and the risk of serious side effects (Table 1). In addition, it is universally accepted that high-dose vitamin A is contraindicated in ABCA4-associated Stargardt dystrophy and RP, where accumulation of toxic A2E can be exacerbated.

Table 1. Current Treatment Options for IRD
Nutritional supplement Adult dosage Indicated IRD Contraindicated IRD. Systemic precautions. Dietary sources
Lutein 12 mg qd RP17 None Dark leafy greens (spinach, kale, Swiss chard, collards), kelp, zucchini, broccoli, corn
DHA 400 mg qd XLRP18,19, STGD60 None Dark fishes (mackerel, tuna, sardines, salmon), halibut, cod, shrimp, scallops
Vitamin A palmitate* 15,000 IU qd RP11 ABCA4-STGD; cautioned in pregnancy, osteoporosis, hepatic dysfunction N/A
*Controversial, please refer to text for discussion
Drug Adult dosage Indicated IRD Notes
Dorzolamide 2% 1 gtt TID RP53,54, Usher53 Responders more likely to have arRP or greater initial retinal thickness,4 risk of rebound CME with prolonged use53
Acetazolamide 500 mg PO qd 250 mg PO BID RP54, Usher55 Risk of rebound CME with prolonged use55,59
Triamcinolone acetonide 0.1 mL (4 mg) intravitreal RP56 For CME refractory to topical or oral therapy
Abbreviations: IRD, inherited retinal dystrophy; DHA, docosahexaenoic acid; IU, international units; qd, daily; gtt, drop; TID, three times daily; QID, four times daily; BID, twice daily; RP, retinitis pigmentosa; XLRP, X-linked RP; STGD, Stargardt dystrophy; arRP, autosomal recessive RP; CME, cystoid macular edema.

On the contrary, the formation of toxic A2E is a target for neuroprotective treatment strategies in ABCA4-Stargardt dystrophy. Indeed, a novel oral synthetic retinoid, ALK-001, has been shown to prevent retinoid dimerization and formation of A2E, and is currently in phase 2 clinical trials (NCT02230228, NCT02402660).

Other supplementation strategies for neuroprotection include the use of lutein, zeaxanthin, and docosahexaenoic acid (DHA), which have all been observed to be abnormally low in the blood of patients with RP (Table 1).13,14 Lutein and zeaxanthin are the two main carotenoids in macular pigment that are thought to reduce oxidative damage by absorbing blue light.15

The omega-3 fatty acid DHA is the most abundant OS phospholipid constituent that can act as an antioxidant and mediate cell death. Supplementation with either lutein or DHA has been shown to slow the decline of visual fields in patients with RP or X-linked RP, respectively.14,16-19 The effect of DHA in Stargardt dystrophy is currently being studied in phase 1 clinical trials (NCT00060749).

Another example of a semitargeted approach is valproic acid, which was initially identified in high-throughput studies screening for drugs that could potentially mitigate the misfolding of rhodopsin due to mutations in RHO associated with autosomal dominant RP.20

Retrospective case series reporting off-label use of oral valproic acid in patients with various types of IRD have revealed contradictory results.21,22 The effect of valproic acid in autosomal dominant RP will hopefully be elucidated in phase 2 clinical trials currently nearing completion (NCT01233609).

In addition to oral supplements and medications, the strategy of slowing retinal degeneration can also be delivered intraocularly, utilizing cell and gene-based platforms. While the holy grail and future of stem cell therapy is the revival of visual function by retinal tissue replacement (see Strategy #3), most cell-based clinical trials use various derived stem cells with the intention of slowing degeneration perhaps via neurotrophic interactions or secretion of retinal protective factors.

The first cell-based clinical trials using ciliary neurotrophic factor (CNTF)-secreting encapsulated cell implants to promote photoreceptor survival showed no significant benefits in patients with RP or achromatopsia,23-25 although long-term follow-up studies are ongoing.

Current clinical trials studying the neurotrophic or neuroprotective effects of other cell-based therapies include the intravitreal injection of autologous CD34+ bone marrow-derived stem cells (NCT01736059), or the intravitreal and subretinal delivery of retinal progenitor cells (NCT02320812, NCT02464436).

While clinical trials for gene-based delivery of neurotrophic factors is not yet active, one promising technique currently being developed will use viral vectors to deliver a gene, Nxnl1, which encodes two isoforms of the rod-derived cone viability factor that promotes cone cell survival and reduces oxidative stress byproducts.26


Stopping disease progression in IRD consists of the direct intervention of the genetic mutation through retinal gene replacement and/or gene suppression techniques. Thus, this strategy is intrinsically only applicable to cases of IRD for which the genetic etiology is known and the diagnosis has been confirmed with genetic testing.

Autosomal and X-linked recessive IRDs are typically associated with a loss-of-function protein, which is well-suited for treatment with retinal gene replacement. By comparison, autosomal dominant IRDs are fundamentally more difficult to treat, requiring not only retinal gene replacement, but also the development of even more sophisticated techniques to suppress the dominant negative or toxic effects of the mutant gene. Thus, recessive IRDs are the focus of current retinal gene therapy clinical trials, which are discussed as follows (Table 2).

Table 2. Current Gene Therapy Clinical Trials for IRD in the United States
Leber congenital amaurosis (LCA)
RPE65 / (AAV2) I Active, not recruiting Samuel G. Jacobson: U. Florida, UPenn 00481546
RPE65 / (AAV2) I Active, not recruiting Spark Therapeutics: CHOP 00516477
RPE65 / (AAV2) I/II Active, not recruiting AGTC: OHSU Casey Eye Institute, U. Mass 00749957
RPE65 / (AAV2) III Active, not recruiting Spark Therapeutics: CHOP, U. Iowa 00999609
Choroideremia (CHM)
CHM / (AAV2) I/II Recruiting Spark Therapeutics: Mass Eye and Ear, U. Penn, CHOP 02341807
CHM / (AAV2) II Recruiting Byron Lam: Bascom Palmer 02553135
X-linked retinoschisis (XLRS)
RS1 / (AAV8) I/II Recruiting NEI: NIH Clinical Center 02317887
RS1 / (AAV2tYF) I/II Recruiting AGTC: OHSU Casey Eye Institute, Mass Eye and Ear, U. Michigan, Retina Foundation of the Southwest 02416622
Achromatopsia (ACHM)
CNGB3 / (AAV2tYF) I/II Recruiting AGTC: OHSU Casey Eye Institute, VitreoRetinal Associates, Bascom Palmer, Pangere Center, Medical College of Wisconsin 02599922
Stargardt (STGD)
ABCA4 / (EIAV) I/II Recruiting Sanofi: OHSU Casey Eye Institute, Baylor 01367444
Usher syndrome (USH)
MYO7A / (EIAV) I/II Recruiting Sanofi: OHSU Casey Eye Institute 01505062
Retinitis pigmentosa (RP) – Optogenetics
Channelrhodopsin-2 (ChR2) / (AAV) I/II Recruiting RetroSense Therapeutics: Retina Foundation of the Southwest 02556736
Modified from Ku et al.61 Abbreviations: IRD, inherited retinal degenerations; RPE65, retinal pigment epithelium-specific protein 65kDa; AAV, adeno-associated virus; ABCA4, ATP-binding cassette, sub-family A, member 4; EIAV, equine infectious anemia virus; MYO7A, myosin VIIA; CHM, choroideremia, rab escort protein 1; RS1, retinoschisin 1; CNGB3, cyclic nucleotide gated channel beta 3; U. Florida, University of Florida, U. Penn, University of Pennsylvania; CHOP, Children’s Hospital of Philadelphia; AGTC, Applied Genetic Technologies Corp.; OHSU, Oregon Health & Science University; U. Mass, University of Massachusetts, Worcester; U. Iowa, University of Iowa; Mass Eye and Ear, Massachusetts Eye and Ear Infirmary; Bascom Palmer, Bascom Palmer Eye Institute; NEI, National Eye Institute; NIH, National Institutes of Health; U. Michigan, University of Michigan; VitreoRetinal Associates, VitreoRetinal Associates, Gainesville, FL; Pangere Center, Pangere Center for Inherited Retinal Diseases.

In 2008, three independent first-in-human retinal gene therapy phase 1 clinical trials were initiated at University College London (UCL), Children’s Hospital of Philadelphia (CHOP), and the Universities of Pennsylvania and Florida (UPenn/UF). Retinal gene replacement therapy utilizing adeno-associated virus (AAV) expressing RPE65 was injected into the subretinal space of one eye in patients with autosomal recessive LCA associated with mutations in RPE65.27-29 Short-term results from all three phase 1 trials reported not only safety, but improved sensitivity to light.

Phase 1/2 dose-escalation studies from CHOP and UPenn/UF further demonstrated improvement in visual acuity, sensitivity, and navigational testing.30-32 After 9-12 months post-treatment, four patients at UPenn/UF even developed a shift in fixation preference to the site of the subretinal injection.33,34 Furthermore, three patients at CHOP underwent subsequent treatment of the contralateral eye without significant inflammatory response, signifying the relative safety of repeated vector exposure.35

Not surprisingly, some limitations of this first generation RPE65 retinal gene replacement have arisen in the long-term results of the phase 1/2 trials. At UPenn/UF, three patients who had the largest improvement of regional retinal sensitivity at 1-3 years also had subsequent contraction of retinal sensitivity at 5-6 years post-treatment.36

A similar trend was noted at the three-year follow-up in all patients treated at UCL.27 The highly anticipated phase 3 results from CHOP are still pending publication, though a recent press release reported improved bilateral mobility testing after one year post-treatment.37

The success of these three pivotal clinical trials in RPE65-LCA have paved the way for the development of retinal gene replacement phase 1/2 clinical trials for other autosomal recessive IRDs (Stargardt dystrophy, Usher syndrome, achromatopsia) and X-linked recessive IRDs (choroideremia, retinoschisis). Similar to LCA, gene delivery for choroideremia, X-linked retinoschisis (XLRS), and achromatopsia also utilize the most commonly-used vector, AAV. However, the ABCA4 and MYO7A genes associated with Stargardt dystrophy and Usher syndrome type 1B, respectively, exceed the 4.7 kb cassette size limit of the AAV vector.

Consequently, gene therapy for ABCA4-Stargardt dystrophy and MYO7A-Usher syndrome require the greater capacity of the equine infectious anemia virus (EIAV) vector. Nearly all retinal gene therapy requires vitreoretinal surgery to deliver the gene-encoding vector to the outer retina via a subretinal injection. The only exception is for XLRS, in which vector delivery to the macula and schisis areas is sufficient with an intravitreal injection.38,39

Results of early findings from these ongoing studies have yet to be published. However, the choroideremia gene therapy clinical trials originated from the United Kingdom, where studies sponsored by the University of Oxford have already demonstrated improved retinal sensitivity in five of six patients and improved visual acuity in patients with the worst baseline.40

While clinical trials for retinal gene replacement in recessive IRD are expanding, promising techniques for the correction and suppression of genetic mutations in autosomal dominant IRD (e.g. RNA-interference, zinc finger nucleases, TALENs, and CRISPR/Cas9) continue to be developed and will undoubtedly be brought to clinical trials in the very near future.41-44


Reviving visual function in patients with IRD will require the replacement of lost retinal tissue or the artificial substitution of photoreceptor function. These strategies generally apply to patients with more advanced disease and vision loss, who are less likely to benefit from neuroprotection or gene therapy.

The ultimate goal of stem cell research is the ability to generate stable differentiated viable tissues, which can be anatomically and functionally reintegrated back into the body. This is distinct from other stem cell-based research aimed at delivering neutrophic factors to slow retinal degeneration (see Strategy #1). With regard to the revival of visual function in IRD, the current focus of stem cell therapy has been to deliver stem cell-derived RPE cells back into regions of atrophy.

There is currently one phase 1/2 clinical trial with the goal of implanting human embryonic stem cell-derived RPE cells into the subretinal space of patients with Stargardt dystrophy (NCT01345006). Published results so far have revealed anatomical changes in the implant area that are suggestive of RPE-like engraftment.45

Specifically, the treated retina showed increased pigmentation that correlated with a hyper-reflective layer along Bruch’s membrane on OCT, but these characteristics are currently of uncertain significance. Confirmation that the pigmented area truly represents viable and functional RPE cells will require further exploration.

Substitution for photoreceptor function is another way to revive visual function in patients with advanced disease. The two methodologies currently in clinical trials are optogenetics and retinal prosthetics.

Optogenetics utilizes gene therapy techniques to induce retinal bipolar or ganglion cells to express light-sensitive opsins with the goal of replacing the visual function of the degenerated photoreceptors.46,47 For patients with RP, there is currently a phase 1/2 clinical trial for optogenetics in which the gene for channelrhodopsin-2, a cation channel derived from the green alga Chlamydomonas reinhardtii, is delivered within an AAV vector via intravitreal injection (Table 2).

Retinal prosthetics are devices that substitute for degenerated photoreceptor function by electrically stimulating the visual pathway at the level of the residual inner retina. The Argus II (Second Sight, Sylmar, CA) system consists of an epiretinal 60-electrode array, which stimulates the retina using visual information fed from a glass-mounted camera and video processing unit.

The result of this electrical stimulation of the retina translates to the perception of patterned phosphenes, representing contextual information for navigation. Indeed, ongoing phase 2 studies in these patients have shown safety,48 improved mobility,49 and spatial motor skills.50 This is the first retinal prosthetic that has been FDA-approved for humanitarian use in patients with RP and bare light perception in the worst-seeing eye.


Chronic cystoid macular edema (CME) can be relatively common in RP (~11-49% of cases),51,52 as well as Usher syndrome. The pathophysiology of CME in IRD is still unknown, but it is thought to be distinct from other common causes of CME such as that due to diabetes, uveitis, or neovascularization.

While there is no gold standard for treatment, retrospective case series have shown that topical or oral carbonic anhydrase inhibitors and intravitreal corticosteroids can reduce CME in RP (Table 1).53-56

The use of intravitreal anti-vascular endothelial growth factor (VEGF) agents may also reduce CME in RP.57 However, its widespread use is tempered by the fact that VEGF levels are already lower than normal in the eyes of patients with RP.58

Moreover, there are unknown long term consequences of anti-VEGF in IRDs pertaining to vascular attenuation and retinal atrophy. That being said, the side effects of the aforementioned medications must constantly be weighed against the benefits of treatment, which are often limited by tachyphylaxis and the lack of correlation with visual function improvement.53,59

There is a need for additional therapeutic options for CME in IRD, and the following agents are currently in clinical trials: topical interferon gamma-1b (NCT02338973), oral minocycline (NCT02140164), and intravitreal aflibercept (NCT02661711).


Inherited retinal degenerations are a heterogeneous group of disorders in which accurate diagnosis can be inherently challenging due to the relatively low prevalence, high variability of presentation, and need for specialized visual diagnostic equipment.

Even though the technology for genetic testing has advanced greatly over the past years, a high degree of clinical suspicion and pretest probability is still vital for guiding genetic testing and interpreting the results.

The early diagnosis and genetic confirmation of IRD is not only important so patients may be offered a choice of participation in clinical trials, but any potential treatment will likely yield maximum benefits during the early phase of the disease.

As the era of targeted therapies becomes a reality, the goal of arresting the disease process and restoring retina function will ultimately require combinations of all strategies tailored to each patient with IRD. RP


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