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Retinitis pigmentosa: for professionals


  • Autosomal dominant
  • Autosomal recessive
  • X-linked recessive
Less common inheritance patterns:
  • Mitochondrial
Genes involved (OMIM No.)Over 80 genes have been identified to cause syndromic and non-syndromic RP, with the most common being:
  • RHO (#180380) in autosomal dominant cases
  • USH2A (#608400) in autosomal recessive cases
  • RPGR (#312610) in X-linked recessive cases
  • Nyctalopia
  • Mid-peripheral “ring” scotoma that constricts over time
  • Progressive loss of BCVA in advanced stages
Ocular features
  • Vessel attenuation
  • Intraretinal bone spicule pigmentation in the mid-periphery with progressive outer retinal and RPE atrophy
  • Optic disc pallor
  • Cystoid macular oedema (CMO) and posterior sub-capsular cataract are common complications
  • Refractive errors (high myopia common in X-linked RP)
  • Atypical RP: sectoral RP and retinal punctata albescens (diffusely scattered white, dot-like lesions)
Systemic featuresRP can be part of a syndrome in 20-30% of patients, with the most common associated conditions:
Key investigations
  • Full-field ERG: Significant reduction in rod responses with less severe reduction in cone responses initially, progressing to general retinal dysfunction over time
  • FAF: Majority display a central ring of hyper-AF demarcating the transition zone between healthy and degenerating outer retina; progressively shrinks over time
  • OCT: Most have preserved foveal outer retinal layers while there is progressive outer retinal thinning and degeneration parafoveally; foveal ellipsoid zone (EZ) length is a reliable marker for disease progression
  • Perimetry (kinetic preferably, or static)
  • Assessment/screening by other specialists may be required if features suggestive of wider systemic involvement are present or based on genetic result
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
  • Voretigene neparvovec (Luxturna) for biallelic RPE65 mutations
  • Correct refractive errors
  • Low vision aids
  • Blue-light screen filters and UV protected sunglasses
  • Monitoring and treating associated complications (CMO and cataract)
  • Healthy diet with fresh fruits and green leafy vegetables
  • Multidisciplinary approach
Therapies under research
  • Gene therapy (phase 1/2)
  • Antisense RNA oligonucleotides (phase 1/2)
  • Neuroprotective agents (phase 2)
  • Optogenetics (phase 1/2)
  • Cell replacement therapy (phase 2b)

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Clinical phenotype

Presenting features

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy. It encompasses a group of progressive conditions characterised by the predominant impairment of rod photoreceptors initially, manifesting as nyctalopia and peripheral scotoma/field loss, followed by subsequent progressive cone involvement and central vision loss. In addition to these cardinal symptoms, some patients may also experience photopsia, photophobia and dyschromatopsia.

Disease onset usually begins with nyctalopia or impaired dark adaptation around adolescence, followed by peripheral visual field (VF) loss which becomes apparent during young adulthood. Patients may initially notice “islands” of scotoma in their mid-periphery, which will coalesce to form an annulus ring. Over time, this ring expands inwards and outwards, eventually resulting in a severely constricted field of vision. Although visual acuity (VA) is relatively preserved in the early stages, it progressively deteriorates later on when cone degeneration ensues.  

Over 80 genes have been identified to cause RP highlighting its genetic heterogeneity. There is also significant intra- and interfamilial phenotypic variability in terms of age of onset, severity of visual dysfunction, disease progression and clinical findings. X-linked RP (XL-RP) usually begins in childhood with a rapid rate of visual decline. The majority of cases are due to RPGR (70-80%)[2-5] and RP2 mutations (5-20%)[2,4,6,7]. Patients harbouring RP2 mutations tend to have a quicker decline in BCVA due to early macular atrophy.[8]

For genes associated with autosomal recessive (AR) and autosomal dominant (AD) RP, a broad spectrum of severity can be observed.[9,10] Some mutation carriers of dominant genes may even be asymptomatic due to incomplete penetrance, and are termed obligate carriers. Heterozygous PRPF31 and RP1 mutations are typical examples.

Hence, predicting disease severity based on Mendelian inheritance patterns alone is of limited value in the current age of molecular genetics. Genetic testing to investigate for the causative gene can provide a more accurate prognosis for patients. 

Pathogenic mutations in some causative genes can lead to both AD and AR forms, where the AR phenotypes may overlap with Leber Congenital Amaurosis (LCA)/Early-onset Severe Retinal Dystrophy (EOSRD). Some examples include:

  • RDH12 (more common in the recessive form leading to LCA/EOSRD)
  • RHO (AR-RP is uncommon; only 4 variants–all in homozygous forms, have been reported to cause a recessive phenotype)
  • RP1 (more commonly associated with AD-RP)
  • RPE65 (more common in the recessive form leading to LCA/EOSRD)

Fundal appearance

Patients with RP typically present with the following fundal features:

  • Optic disc pallor
  • Vessel attenuation
  • Intraretinal bone spicule pigmentation in the mid-periphery with varying degrees of retinal pigment epithelium (RPE) atrophy
The right retina of a patient with retinitis pigmentosa showing the typical features, a pale circle signifying the optic nerve, with diffuse liner black pigments deposited in the peripheral retinal in a circumferential pattern surrounding the optic nerve.
Typical RP fundal phenotypes with disc pallor, vessel attenuation and bone-spicule pigments in the mid-periphery with retinal atrophy

However, these features may not be apparent in the earliest stages of the disease. Instead, there may be non-specific signs such as[1]:

  • Abnormal/impaired foveal reflex
  • Subtle RPE mottling/areas of depigmentation

In some cases, the fundus may not display the typical RP features. These are collectively called atypical RP and can be caused by mutations in multiple genes. Examples include:

  • Sectoral RP– A stable/slowly progressive phenotype characterised by localised RP changes usually confined to the inferior quadrants; patients tend to be asymptomatic or complain of an altitudinal field loss instead of nyctalopia (majority of cases are associated with heterozygous RHO mutations)[11,12]
  • RP sine pigmento– This is a historical term that describes the lack of retinal pigmentation or early stages of RP. It now has limited value with modern molecular genetics as the lack of bone spicules does not correlate with underlying cause or severity
  • Retinal punctata albescens– A phenotype characterised by diffuse, round and white punctate deposits at the level of the RPE in the mid-periphery (usually associated with RLBP1 mutations)
The retina of a patient with sectoral retinitis pigmentosa. This means only part of the retina is affected, in this case the bottom half of the retina has the typical black coloured pigments indicating retinal degeneration.
Inferior sectoral retinitis pigmentosa in a patient with autosomal dominant RHO mutation. Bone spicules are seen on the inferior retina on wide field colour fundus photography (A). There is generalised retinal degeneration of the inferior retina seen on FAF imaging (B). There is a hypoautofluorescent ring centrally, which is surrounded by a hyperautofluorescent ring.
The retina of a patient with retinitis pigmentosa due to mutations in the RLBP1 gene. There are multiple white dot-like deposits throughout the retinal periphery.
A patient with confirmed ballelic RLBP1 mutation displaying a fundal phenotype that can be described as retinal punctata albescens. Multiple punctate white dots are visible in the periphery. There is circumferential atrophy near the optic disc.

Other ocular features

Apart from retinal degeneration, patients may have the following ocular features which can lead to further visual deterioration:

  • Early-onset cataracts (typically posterior sub-capsular)
  • Cystoid macular oedema (up to 50% of patients may be affected)[13]
  • Macular holes and epiretinal membranes
  • Refractive errors: XL-RP is typically associated with high myopia while hypermetropia is seen with CRB1 mutations)
An RP patient with cystoid macular oedema

Associated extraocular features

In 20-30% of patients, RP may be a manifestation of a wider systemic conditions which may require input from other specialties.[1] Early recognition of some of these conditions can be life-saving. Some notable examples are:

  • Usher syndrome (most common form of syndromic RP)
  • Bardet-Biedl syndrome
  • Refsum disease — an AR condition characterised by phytanic acid oxidase deficiency due to PHYH mutations, resulting in RP, peripheral neuropathy, ataxia and sometimes cardiac arrhythmia
  • Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC) — A progressive neurodegenerative disorder due to compound heterozygous or homozygous mutations in the ABHD12 gene. It is characterised by cataract (predominantly posterior sub-capsular), RP, sensorineural hearing loss, ataxia and sensorimotor neuropathy
  • Kearns-Sayre syndrome — a mitochondrial disorder characterised by progressive external ophthalmoplegia, RP, cardiac arrhythmia and ataxia

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Pathogenic mutations in more than 80 genes have been identified so far that account for about 50-70% of cases.[12,14-16] The most common causative genes are:

  • RHO (AD-RP)
  • USH2A (AR-RP; most common cause of type II Usher syndrome)
  • RPGR (XL-RP)

Many of the identified causative genes encode proteins that play vital functional and structural roles in the photoreceptors and/or the RPE.

General functionGenes
PhototransductionCNGA1, CNGB1, DHDDS, GNAT1, GUCA1B, PDE6A, PDE6B, PDE6G, RHO, SAG
Visual cycleABCA4, LRAT, RBP3, RDH12, RGR, RLBP1, RPE65
Photoreceptor morphogenesis/developmentARHGEF18, CRB1, NEK2, SEMA4A, SLC7A14, TOPORS, ZNF408, ZNF513
Interphotoreceptor matrixIMPG2
Photoreceptor ciliary development and transportAGBL5, AHI1, ARL2BP, ARL3, ARL6, BBS1, BBS2, BBS9, C2orf71, C8orf37, CDHR1, CLRN1, EYS, FAM161A, FSCN2, IFT140, IFT172, KIZ, MAK, OFD1, POMGNT1, PROM1, PRPH2, RP1, RP1L1, RP2, RPGR, SPATA7, TOPORS, TTC8, TULP1, USH2A
Retinal homeostasisBEST1, CA4, CERKL, CLN3, HK1, HGSNAT, IDH3B, KLHL7, MERTK, MVK, PANK2, REEP6
Transcription factor/nucleotide synthesisCRX, IMPDH1, NEUROD1, NR2E3, NRL, SAMD11
RNA splicingCWC27, DHX38, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, RP9, SNRNP200
Unknown functionADGRA3, EMC1, KIAA1549, PRCD

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations


1) Fundus autofluorescence imaging (FAF)

FAF findings are variable in RP but most patients display a central hyperautofluorescent ring that constricts over time. The ring demarcates a transition zone between healthy and degenerating retina which can be appreciated clearly on optical coherence tomography (OCT). The ring diameters (horizontal and vertical) are reliable surrogate markers for visual function.[17-21]

Wide field FAF imaging (A) and OCT scan of the macula (B) of a patient with autosomal dominant RHO mutation. There is a central hyperautofluorescent ring that indicates the border between preserved and diseased outer retina. The central outer retinal layers are relatively preserved, and gradually becoming thinner with increasing eccentricity.

2) Optical coherence tomography (OCT)

Within the hyperautofluorescent ring, the outer retinal layers are relatively preserved while there is disruption of the ellipsoid zone (EZ) and outer nuclear layer (ONL) thinning across the ring. Outer retinal and RPE atrophy are observed beyond the ring.[22] The foveal EZ length coincides with the constriction of the hyperautofluorescent ring and correlates well with central visual function.[18,23]

In addition, CMO can be easily detected on OCT and inform clinicians about treatment response.

3) Kinetic perimetry

An annulus scotoma is present in the mid-periphery which gradually constricts over time, leaving a small residual central island.

4) Electrophysiology

In full-field electroretinogram (ERG), the dark-adapted stimuli (DA 0.01, DA 3 and DA 10 flashes) predominantly measure rod function. The DA 0.01 dim flash elicits a rod-specific response while the stronger DA 3 and DA 10 flashes have some cone contribution. Cone function is selectively assessed with light-adapted stimuli (LA 3 flash and 30 Hz flicker).

Subnormal and delayed a- and b-waves (rods more severely affected than cones; rod-cone dystrophy) can be observed during early stages of the disease.  Both responses gradually deteriorate over time and become unrecordable in the advanced stages.

Pattern ERG (PERG) is a useful tool to assess macular function as the responses are mainly driven by the macular cone photoreceptors. Early and significant reduction in PERG responses can be observed in patients with RP2 mutations.  


As RP can be the first manifestation of many syndromic cases, careful systemic enquiry during history taking and an increased awareness of potential extraocular involvement are crucial in identifying patients that may require input from other specialities. In children, consider early referral to paediatrics for further assessment of development and any systemic features.

Genetic testing can also flag up patients that may require systemic assessment but clinical findings must be taken into context when interpreting the results as some genes are associated with both syndromic and non-syndromic RP (e.g. USH2A).

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Although RP can be inherited in all forms of Mendelian and rarely non-Mendelian (e.g mitochondrial) modes, the majority of patients are simplex cases with no family history at presentation.[24] Therefore, genetic testing should be undertaken to obtain a molecular diagnosis which can help facilitate genetic counselling, provide accurate advice on prognosis and future family planning, direct further clinical management and aid in clinical trial participation.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing

Most sporadic patients are found to have autosomal recessive inheritance from genetic testing and further parental segregation of causal variants.[12,15]

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1) Supportive management

  • Correcting any refractive errors
  • Referral to low vision services
  • Directing patients to supporting organisations 
  • Encourage the use of assistive technology that may improve quality of life 
  • Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
  • Blue light screen protectors on mobile devices or computer screens*
  • UV protected sunglasses
  • Treating associated ocular abnormalities such as cataracts and CMO

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

Cataract surgery may benefit some patients but careful case selection and detailed discussion with patients about their expectations and possible risks are crucial to achieving a good outcome. Up to 50% of patients may not actually benefit from cataract removal.[25-28] Post-operative visual outcome can be predicted based on pre-operative BCVA, central macular thickness and foveal outer retinal (EZ and external limiting membrane) integrity.[26,28] The most common post-operative complications are posterior capsular opacification and CMO.

Even without surgery, CMO can be observed in a proportion of RP patients. It is usually self-limiting and often does not affect visual function. However, there are various treatment options for patients who are symptomatic though response is highly variable:

  • Topical carbonic anhydrase inhibitors (CAIs) such as dorzolamide should be used as first line treatment[13]
  • Oral CAIs are an alternative but are associated with higher risk of systemic side effects
  • Steroids (intravitreal/sub-tenon triamcinolone, intravitreal dexamethasone [Ozurdex] or oral deflazacort) can be used if not responding to CAIs but the risks of glaucoma and cataract should to be considered
  • Intravitreal anti-VEGF (associated with good anatomical outcome but level of visual improvement varies)[29-31]

2) Gene therapy

Patients with confirmed biallelic RPE65 mutations in the UK (and other countries around the world) are now able to receive retinal gene therapy with voretigene neparvovec (Luxturna) under the National Health Service (NHS). A normal healthy copy of the RPE65 gene is packaged into a recombinant adeno-associated virus (AAV) serotype 2 vector which is then injected sub-retinally to replace loss-of-function variants in the photoreceptors.

This followed the success of a phase 3 trial which demonstrated that 65% of participants injected with Luxturna were able to navigate around an obstacle course at reduced light levels compared to controls. This improvement has been sustained up to 4 years after vector administration. The safety profile of sub-retinal AAV2 injections has been well established in numerous trials (Hauswirth et al 2008, Bainbridge et al 2008, Jacobson et al 2012 and Weleber et al 2016). The side effects frequently reported in trials are related to the surgical procedure itself, which include:

  • Subconjunctival haemorrhage
  • Ocular hyperaemia
  • Post-operative ocular inflammation
  • Ocular hypertension

Treatment centres in the UK currently offering Luxturna


A multidisciplinary approach is required if a child is affected by syndromic RP such as Usher syndrome or Bardet-Biedl syndrome.

Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.

Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

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Family management and counselling

RP can be inherited in the following Mendelian and non-Mendelian patterns:

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis. However, most patients tend to be simplex cases on presentation and thus may make counselling challenging prior to genetic testing.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

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Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in RP

1) Gene therapy

Several AAV-based gene therapy trials are currently underway for different causative genes.

GeneRegistry no.Clinical phaseInterim data/published results
MERTKNCT 014821951Ghazi et al 2016, Saudi Arabia
PDE6BNCT 033281301/2Ongoing with no preliminary data
RLPBP1NCT 033746571/2Ongoing with no preliminary data

2) Antisense RNA oligonucleotides (AONs)

AONs are small molecules that works in an allele-specific manner. It binds complementarily to their target messenger RNAs (mRNA) to block the transcription of a mutant allele or correcting splicing defects at the pre-mRNA level.[32] AONs are usually delivered via intravitreal injections.

It is currently being trialled in two major RP genes: the p.Pro23His RHO mutation (NCT 04123626; AURORA) and mutations in exon 13 of USH2A (NCT 03780257; STELLAR).


The p.Pro23His mutation in RHO is highly prevalent in the US among those of European origin.[33] The mutant transcript exerts a dominant negative effect on the wild-type (normal) allele and thus suppresses the function of the wild-type rhodopsin protein. The AON currently being trialled, QR-1123 works by obstructing the transcription of the mutant allele whilst preserving wild-type protein production.[34]


The most common pathogenic variants causing syndromic and non-syndromic RP in USH2A, c.2299Del, p.Glu767Serfs*21 (usually associated with type II Usher ,syndrome)[35,36] and c.2276 G>T, p.Cys759Phe (a retinal disease allele)[37,38] are both located in exon 13. Pre-clinical studies have demonstrated that skipping of exon 13 results in the production of a shortened but functional Usherin protein.[39,40] Interim analysis of the AON currently being trialled (QR-421a) showed that the treatment was well-tolerated and improvements in both functional and anatomical parameters were observed in two participants.

A mutation in intron 40 (c.7595-2144A>G) causes aberrant splicing of the USH2A pre-mRNA at this region, introducing a pseudo-exon (PE40) with a premature stop codon. Pre-clinical studies of AONs with human fibroblast cells showed significant correction of this splicing defect but its therapeutic effect could not be assessed in detail in a zebrafish model due to differences between the human and zebrafish splicing machinery

3) Neuroprotective agents

Neuroprotection encompasses various strategies with the common goal of slowing down or halting photoreceptor degeneration.

(a) Oral N-acetylcysteine (NAC)/N-acetylcysteine-amide (NACA)

There are significantly more rods than cones in the retina. It is hypothesised that in RP, oxygen consumption is greatly reduced with primary rod death, resulting in large amounts of oxygen free radicals being generated. This in turn leads to subsequent cone death due to oxidative stress as the antioxidant defence system becomes overwhelmed.[41] Both NAC and its prodrug NACA are potent antioxidants which can minimise intracellular damage, and hence preserve cone structure and function for longer.[42,43] A phase 1 trial of daily oral NAC intake for 6 months (FIGHT-RP1) showed a dose-dependent improvement in mean macular sensitivity during the treatment period. The drug was well-tolerated up to 1800mg twice daily and the most commonly reported side effects were gastrointestinal related. A phase 2 clinical trial using NACA is being planned.

(b) Neurotrophic factors

Neurotrophic factors are endogenously secreted molecules that stimulate cell growth, proliferation, differentiation and regeneration.[44] Multiple trophic factors have been shown to slow photoreceptor loss in animal models but only two have been/are being translated to human clinical trials.[45-47]

The ciliary neurotrophic factor (CNTF) was investigated in two separate phase 2 trials for both early and late stage RP. CNTF was continuously released from an intraocular implant containing RPE cells transfected with the CNTF gene. Although the implant was safe and CNTF was continuously released, neither functional nor structural improvement were observed in the long-term.

The rod-derived cone viability factor (RdCVF), first described by Léveillard et al, promotes cone survival by stimulating aerobic glycolysis to meet the metabolic demands of daily cone outer segment renenwal.[48] Systemic and intravitreal delivery of RdCVF in mouse models resulted in structural and functional improvement of cones, providing proof-of-concept for a human clinical trial.[49]

(c) Tauroursodeoxycholate acid (TUDCA)

TUDCA is a taurine conjugate of its original derivative ursodeoxycholic acid (UDCA). Both are naturally occuring bile acids found in hibernating bears. Synthetic UDCA is an FDA (US Food and Drug Administration) and NICE (National Institute for Health and Care Excellence) approved treatment for primary biliary cholangitis. TUDCA exerts a neuroprotective effect on photoreceptors through multiple pathways[50]:

  • Preventing cell apoptosis
  • Reducing endoplasmic reticulum stress by improving protein folding capacity
  • Reducing production of reactive oxygen species
  • Anti-inflammatory effect

Pre-clinical studies in various RP mice models (rd1, rd10, Bbs1, P23H and Rpgr) have shown that intraperitoneal or subcutaneous TUDCA injections resulted in significant preservation of photoreceptor structure and function. There are ongoing clinical trials for TUDCA in other conditions  (ulcerative colitis, various neurodegenerative conditions, diabetes and amyloidosis) but not in inherited retinal dystrophies.

4) Optogenetics

Optogenetics aims to restore some level of vision in patients with advanced RP by conferring photo-detection abilities to the surviving inner retinal cells. This is achieved by transfecting cells with genes encoding for light-sensitive ion channels or pumps, such as channelrhodopsin (ChR) and halorhodopsin which are derived from micro-organisms.[51] ChR is a light-gated cation-channel derived from the green alga Chlamydomonas reinhardtii while halorhodopsin is a light-gated anion-pump found in halobacteria.[52]

Current clinical trials are mainly investigating the safety and tolerability of intravitreal ChR injections (NCT 02556736, NCT 03326336, NCT 04278131) in patients with end stage RP.

5) Cell replacement therapy

The replacement of damaged RPE cells with stem cells have been investigated in multiple trials, mainly for ABCA4-retinopathies and age-related macular degeneration (AMD). It involves sub-retinal transplantation of RPE cells derived from human embryonic pluripotent stem cells (hESCs) or less commonly, human-induced pluripotent stem cells (hIPSCs).  

Other cell types that have been/are being investigated include adult stem cells (usually bone marrow stem cells) and progenitor cells (retinal and neural). Instead of replacing the damaged photoreceptors and/or RPE, they exert a neuroprotective effect on remaining photoreceptors through the secretion of neurotrophic factors.

More details can be found in the section “stem cells as a potential treatment for eye diseases”.

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Further information and support

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Updated on January 17, 2021

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