Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBOH16)

• DTT 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
• Gene Name: RPE65
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Carboxylic ester hydrolase
• UniProt ID: RPE65_HUMAN
• TTD ID: T17502
• EC Number: EC 3.1.1.64
• Sequence:
  MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHL
  FDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFF
  SYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAH
  PHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYV
  HSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYL
  NNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKA
  PQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQ
  INYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALE
  EDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS
• 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).
• KEGG Pathway: Retinol metabolism (hsa00830)
• Reactome Pathway: The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
• BioCyc Pathway: MetaCyc:ENSG00000116745-MON

Molecular Interaction Atlas (MIA) of This DTT

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AAV2-hRPE65v2	DMJNSLU	Ocular disease	1F00.1Z	Phase 3	[1]
Emixustat	DMH8VMP	Age-related macular degeneration	9B75.0	Phase 2/3	[2]
AAV-RPE65	DMAH6UJ	Leber congenital amaurosis	9B70	Phase 1/2	[3]
Leber's congenital amaurosis gene therapy	DMFHV9L	Leber congenital amaurosis	9B70	Phase 1/2	[4]
TgAAG76	DMNKLZM	Blindness	9D90	Phase 1/2	[5]

References

• [1] AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012 Feb 8;4(120):120ra15.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of MeiraGTx.
• [4] 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.
• [5] 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.