Update on the Diagnosis and Management of Pediatric Retinal Disease: Precision Medicine

Part 3 of a 3-part series on non-ROP pediatric retinal conditions.


Precision medicine is defined by the National Institutes of Health as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.” The 2015 federal establishment of a Precision Medicine Initiative emphasizes the recognition of its importance in the development of new medicines and therapeutic approaches for the future.

Chorioretinal dystrophies and degeneration lead to photoreceptor death, resulting in irreversible vision loss. Examples of such disorders are listed in Table 1, and many of these conditions are associated with single gene mutations. The eye has been described as an ideal target for novel therapies due to its ease of accessibility, optical transparency, availability for noninvasive monitoring, significant compartmentalization, and immune privileged status.1

Table 1: Chorioretinal Dystrophies and Syndromes
Nonsyndromic rod-cone dystrophies Leber congenital amaurosis
Retinitis pigmentosa
Retinitis punctata albecens
Syndromic rod-cone dystrophies Usher syndrome
Bardet-Beidl syndrome
Joubert syndrome
Syndromic cone-rod dystrophies Alstrom syndrome
Jalili syndrome
Batten disease
Macular dystrophies ABCA4-related retinopathy (Stargardt)
BEST1-related retinopathy
PRPH2-related retinopathy (pattern dystrophy)
EFEMP1-related retinopathy (dominant drusen)
Rod dysfunction syndromes (stationary) Childhood stationary retinal dysfunction
Fundus albipunctatus
Oguchi disease
Cone dysfunction syndromes Achromatopsia
Blue cone monochromacy
Oligocone trichomacy
Red/green X-linked color blindness
Choroidal dystrophies Choroideremia
Gyrate atrophy
Bietti crystalline dystrophy

In this final part of the series, we discuss recent developments in precision medicine and retinal implants for the treatment of chorioretinal dystrophies and syndromes. Specifically, we discuss the potential role of gene therapy, stem cell therapy, and retinal implants in the management of pediatric retinal diseases.

Ru-ik Chee, MD, and Mrinali Patel Gupta, MD, are from the Department of Ophthalmology, Weill Cornell Medical College, New York, New York. Ann-Marie Lobo, MD, and R.V. Paul Chan, MD, are from the Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Illinois. The authors report no disclosures related to this article. Dr. Chan can be reached at The authors would like to acknowledge Mark Pennesi, MD, PhD, of Casey Eye Institute, Oregon Health & Science University in Portland, Oregon, for his contribution to the table and content in this article.


Gene therapy holds promise for halting pathologic processes that lead to tissue damage. Retinitis pigmentosa (RP) is a group of inherited disorders associated with progressive degeneration of photoreceptors, predominantly rods, resulting in severe vision impairment. Retinal findings in RP include characteristic retinal pigmentary changes and arteriolar attenuation (Figure 1). More than 70 mutated genes have been identified to cause RP.1 It may occur with isolated ophthalmic findings or as part of a syndrome. In Usher syndrome, RP is associated with deafness. In Bardet-Biedl syndrome, RP is associated with developmental delay and hypogonadism. It may also be associated with Refsum disease, Alport syndrome, Kearns-Sayre syndrome, abetalipoproteinemia, Batten disease, Alstrom disease, and Cockayne syndrome, among others.

Figure 1. Fundus images of a pediatric patient with RP. There is involvement of the right (A) and left (B) eyes, with characteristic retinal pigmentary changes and arteriolar attenuation. Focal areas of blurring centrally in both eyes are secondary to the presence of posterior subcapsular cataracts, commonly present in retinitis pigmentosa.

Achromatopsia is associated with mutations in genes related to cone phototransduction such as cyclic nucleotide-gated ion channel B3.2 Choroideremia is associated with mutations in the CHM gene, leading to rab escort protein-1 deficiency, subsequently resulting as degeneration of the choroid, RPE, and neurosensory retina.3,4 X-linked retinoschisis is associated with mutations in retinoschisin, which plays a role in retinal architectural organization and synaptic structure.5

The National Eye Institute is currently involved with active gene therapy clinical trials for Leber congenital amaurosis (LCA), achromatopsia, choroideremia, X-linked retinoschisis, RP, Usher syndrome, and Stargardt disease. Leber congenital amaurosis has been associated with numerous genetic mutations affecting multiple visual pathways. One subtype, retinal pigment epithelium 65-associated LCA, has received widespread attention after the success of early clinical trials in 2008 that demonstrated the safety and efficacy of adeno-associated virus (AAV)-mediated gene supplementation therapy that improved vision in LCA patients.6-9 Subsequent longer-term follow-up studies affirmed the relative safety of AAV-mediated gene therapy.10,11

Although gene therapy technologies are promising, certain limitations exist, such as (a) inability of many vectors to cross anatomic barriers in the eye such as the internal limiting membrane, (b) immunogenicity of viral vectors, and (c) limitations in cargo size, which for example prevents packaging of both the RNA guide and the Cas protein components of clustered regulatory interspaced short palindromic repeats (CRISPR/Cas) technology, a preclinical gene-editing technology, within a single AAV.


Stem cells have the potential to differentiate into multiple cell types, as well as self-renew indefinitely in their undifferentiated state. Stem cells are commonly involved in tissue homeostasis, and harbor large regenerative potential. Clinical trials in stem-cell–derived therapy are ongoing in RP and Stargardt disease, which lead to photoreceptor and RPE degeneration.12,13 Retinal regeneration is hypothetically induced through cell replacement therapy with transplantation of directly differentiated pluripotent stem cells, or through stimulation of endogenous retinal stem cells with trophic factors.

Nevertheless, the potential for malignant transformation of stem cells if the cellular differentiation process goes awry should not be taken lightly. The promise of tissue regeneration from stem cell therapy should also not result in abandoning safe evidence-backed investigation of novel therapies. Just this year, the New England Journal of Medicine published 2 articles within the same issue contrasting the early investigational scientific evidence of safety of the use of induced pluripotent stem cells (iPSCs)14 in AMD in one study with another article discussing complications in individuals who were treated with unregulated bilateral intravitreal injections of adipose tissue-derived cells.15 Public awareness and regulation of unethical practices are critical while careful methodical investigation aims to establish a safe and consistent therapeutic option.


Retinal implants have also been used to improve vision, function, and quality of life in patients with retinal degenerations. The Argus retinal implant (Second Sight Medical Products) is a 16-electrode array (4x4) surgically implanted on the epiretinal surface. In 2011, Argus obtained European approval for RP. Argus II contains 60 electrodes in its array (10x60), and it received FDA approval in 2013. The Argus implants have been shown to allow letter and word reading, improve long-term function, and improve spatial-motor performance in patients with profound visual impairment.16

The Alpha IMS device (Retina Implant AG) is a subretinal implant that features 1,520 electrodes (38x40). Increased electrode density has not been shown to provide superior results to the Argus in terms of perceiving large print letters, or reading words in large print.16-18 Instead of electrode density, electrode-tissue interface stimulation, severity of retinal degeneration, cortical remodeling, and the patient’s role in the visual rehabilitation process may have larger limiting effects on final acuity.19-23 Albeit improving function, true spatial resolution remains limited with currently available retinal implants but may improve over time with optimized image processing techniques.24


Management of pediatric retinal conditions requires clear communication of the goals of treatment with patients and their families. Although treatments for pediatric retinal conditions include topical, periocular, and intraocular medications, systemic medications, laser therapy, cryotherapy, and vitreoretinal surgery, close observation may be the most appropriate first course of action. In other cases, such as in some cases of advanced retinoblastoma, enucleation may be necessary to allow an individual the best chance of survival. Coordination of care with pediatric ophthalmologists optimizes visual outcomes. Eye patching and the correction of refractive errors may be required to reduce the risk of amblyopia. Additionally, numerous conditions with retinal manifestations have systemic associations, and conversely, systemic conditions such as diabetes and sickle cell disease are associated with retinal pathology. In either case, recognition for the need for referral, cooperation, and communication with care providers of other medical specialties will be required. Hereditary conditions may additionally require the need for genetic testing and screening of family members.

Novel and groundbreaking treatments for pediatric retinal diseases have been, and are actively being, developed. Retinoblastoma is now a disease in which not only vision, but also life, can be preserved. Anti-VEGF therapy has greatly changed the treatment of adult retinal diseases, and has shown significant potential in pediatric retinal diseases. Precision medicine, stem cell therapy, and retinal implants are primed for significant advancements in the coming years. Immunotherapy may provide new options in the treatment of inflammatory chorioretinal conditions. The spectrum of treatment options we can provide for the treatment of patients both for ROP and non-ROP conditions is burgeoning. RP


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