Target Information

Target General Information

Target ID

T17502 (Former ID: TTDI02295)

Target Name

Retinal pigment epithelium protein (RPE65)

Synonyms

Retinol isomerase; Retinoid isomerohydrolase; Retinal pigment epithelium-specific 65 kDa protein; Meso-zeaxanthin isomerase; Lutein isomerase; All-trans-retinyl-palmitate hydrolase

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Gene Name

RPE65

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Ocular disease [ICD-11: N.A.]

Macular degeneration [ICD-11: 9B75]

Function

Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins. Catalyzes the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol which is further oxidized by 11-cis retinol dehydrogenase to 11-cis-retinal for use as visual chromophore. Essential for the production of 11-cis retinal for both rod and cone photoreceptors. Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid. The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT (By similarity).

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BioChemical Class

Carboxylic ester hydrolase

UniProt ID

RPE65_HUMAN

EC Number

EC 3.1.1.64

Sequence

MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHL
FDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFF
SYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAH
PHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYV
HSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYL
NNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKA
PQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQ
INYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALE
EDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

AAV2-hRPE65v2

Drug Info

Phase 3

Ocular disease

[2]

Emixustat

Drug Info

Phase 2/3

Age-related macular degeneration

[3]

AAV-RPE65

Drug Info

Phase 1/2

Leber congenital amaurosis

[4]

Leber's congenital amaurosis gene therapy

Drug Info

Phase 1/2

Visual disturbance

[5]

TgAAG76

Drug Info

Phase 1/2

Blindness

[6]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 3 Modulator drugs

AAV2-hRPE65v2

Drug Info

[1]

Leber's congenital amaurosis gene therapy

Drug Info

[5]

TgAAG76

Drug Info

[9]

Inhibitor

[+] 1 Inhibitor drugs

Emixustat

Drug Info

[7]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Retinol metabolism	hsa00830	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy

Degree	5	Degree centrality	5.37E-04	Betweenness centrality	6.54E-08
Closeness centrality	1.25E-01	Radiality	1.08E+01	Clustering coefficient	6.00E-01
Neighborhood connectivity	6.00E+00	Topological coefficient	4.29E-01	Eccentricity	14
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Target Affiliated Biological Pathways

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BioCyc

[+] 1 BioCyc Pathways

The visual cycle I (vertebrates)

KEGG Pathway

[+] 1 KEGG Pathways

Retinol metabolism

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Retinol Metabolism

PID Pathway

[+] 2 PID Pathways

Visual signal transduction: Cones

Visual signal transduction: Rods

Reactome

[+] 1 Reactome Pathways

The canonical retinoid cycle in rods (twilight vision)

WikiPathways

[+] 2 WikiPathways

Vitamin A and Carotenoid Metabolism

Visual phototransduction

References

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REF 1

AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012 Feb 8;4(120):120ra15.

REF 2

ClinicalTrials.gov (NCT00999609) Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis. U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT01802866) Safety and Efficacy Assessment Treatment Trials of Emixustat Hydrochloride. U.S. National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT02781480) Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (OPTIRPE65). U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT00749957) Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT00643747) Safety Study of RPE65 Gene Therapy to Treat Leber Congenital Amaurosis. U.S. National Institutes of Health.

REF 7

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 8

Clinical pipeline report, company report or official report of MeiraGTx.

REF 9

tgAAG76, an adeno-associated virus delivered gene therapy for the potential treatment of vision loss caused by RPE65 gene abnormalities. Curr Opin Mol Ther. 2010 Aug;12(4):471-7.

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