RPE65: Role in the Visual Cycle, Human Retinal Disease, and Gene Therapy
Open accessAbstract
RPE65 is an isomerohydrolase expressed in retinal pigment epithelium. It is critical for the regeneration of the visual pigment necessary for both rod and cone-mediated vision. Mutations in human RPE65 cause Leber's congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness. Several RPE65 animal models including two different mouse models and a naturally occurring canine model have been thoroughly characterized to determine the mechanisms that underlie RPE65 associated retinal dystrophies. More recently, substantial effort has gone into designing gene therapies for these diseases. Based on several encouraging reports from animal models, at least three clinical trials are currently underway for the treatment of LCA using modified AAV vectors carrying the RPE65 cDNA and have reported positive preliminary results.
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RPE65 catalyses the conversion of all-trans-retinyl ester to 11-cis-retinol, allowing it to be reused in phototransduction and preventing its conversion to potentially toxic molecules.
“RPE65 catalyses the conversion of all-trans-retinyl ester to 11-cis-retinol, allowing it to be reused in phototransduction and preventing its conversion to potentially toxic molecules.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [108]
The Introduction states that RPE65 converts all-trans-retinyl ester to 11-cis-retinol as part of the visual cycle, which regenerates 11-cis-retinal for vision. Our copy does not say that this conversion prevents formation of potentially toxic molecules. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn RPE65 retinopathy, retinyl esters accumulate in the RPE, leading to its damage.
“In addition, retinyl esters accumulate in the RPE, leading to its damage [7,108,109,110].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [108]
The Introduction states that retinyl esters accumulate in the RPE without RPE65. The RPE65 animal models section reports RPE inclusions and retinal degeneration, but does not establish that ester accumulation causes damage to the RPE itself. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe pathogenesis of RPE65 retinopathy combines local vitamin A deficiency and impaired metabolism, leading to formation of toxic byproducts.
“The pathogenesis, therefore, combines local vitamin A deficiency and its impaired metabolism, which leads to the formation of toxic byproducts.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [108]
The Introduction (page not provided) says RPE65 deficiency substantially reduces 11-cis-retinal and causes retinyl esters to accumulate in the retinal pigment epithelium, supporting impaired retinoid metabolism and a local shortage of a visual-cycle product. The RPE65 animal models section (page not provided) also reports retinyl-ester accumulation, but neither passage says that impaired metabolism forms toxic byproducts or identifies the accumulated esters as toxic. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPathogenic variants in RPE65 result in 11-cis-retinol and subsequently 11-cis-retinal deficiency, which essentially stops the visual cycle.
“Pathogenic variants in RPE65 result in 11-cis-retinol and subsequently 11-cis-retinal deficiency, which essentially stops the visual cycle.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [108]
The Introduction (page unavailable) says RPE65 produces 11-cis-retinol and that, without RPE65, 11-cis-retinal is substantially reduced. The RPE65 associated diseases section (page unavailable) says pathogenic mutations vary in effect: some retain activity and capacity for 11-cis-retinal production. Thus the proposed deficiency is supported, but saying pathogenic variants generally essentially stop the visual cycle overstates the source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFor RPE65, disease severity is associated with the degree of residual enzymatic activity.
“For RPE65 the severity of disease has been associated with the degree of residual enzymatic activity.274,281,557”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [281]
RPE65 is vital for maintaining normal photoreceptor function via trans-retinol conversion.
“RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion; mutations or loss of function are associated with retinitis pigmentosa and are implicated in AMD [21].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [21]
Mutations or loss of function of RPE65 are associated with retinitis pigmentosa and are implicated in AMD.
“RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion; mutations or loss of function are associated with retinitis pigmentosa and are implicated in AMD [21].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [21]
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References 69 · Cited by 162
- Authors
- Cai, X., Conley, S. M., & Naash, M. I.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- Venue
- Ophthalmic Genetics
- Publisher
- Informa UK Limited
- Published
- 2009-01
- Volume
- 30
- Issue
- 2
- Pages
- 57-62
- ISSN
- 1381-6810 (ISSN-L)
- 1744-5094
- PMC
- PMC2821785
- OpenAlex
- W2139761967
- Cited by
- 162
- References
- 69
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 15 · 2023: 12 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 6 · 2018: 8 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 2 · 2013: 5 · 2012: 3
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ophthalmic Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (F32EY018512, R01EY018656, R01EY010609)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- RPE65, visual cycle, retinal pigment epithelium, Leber congenital amaurosis, retinitis pigmentosa, retinal dystrophy, gene therapy, adeno-associated virus vectors, RPE65 mutations, animal models
- MeSH terms
- Retinoid Isomerohydrolase, Animals, Blindness, Carrier Proteins, Disease Models, Animal, Dogs, Eye Proteins, Humans, Retinal Degeneration, Vision, Ocular, Genetic Therapy, cis-trans-Isomerases, Mice
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