Targeting ON-bipolar cells by AAV gene therapy stably reverses LRIT3 -congenital stationary night blindness.
Keiko MiyaderaEvelyn SantanaKarolina RoszakSommer IffrigMeike ViselSimone IwabeRyan F BoydJoshua T BartoeYu SatoAlexa GrayAna Ripolles-GarciaValerie Liliane DufourLeah C ByrneJohn G FlanneryWilliam A BeltranGustavo D AguirrePublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
SignificanceCanine models of inherited retinal diseases have helped advance adeno-associated virus (AAV)-based gene therapies targeting specific cells in the outer retina for treating blinding diseases in patients. However, therapeutic targeting of diseases such as congenital stationary night blindness (CSNB) that exhibit defects in ON-bipolar cells (ON-BCs) of the midretina remains underdeveloped. Using a leucine-rich repeat, immunoglobulin-like and transmembrane domain 3 ( LRIT3 ) mutant canine model of CSNB exhibiting ON-BC dysfunction, we tested the ability of cell-specific AAV capsids and promotors to specifically target ON-BCs for gene delivery. Subretinal injection of one vector demonstrated safety and efficacy with robust and stable rescue of electroretinography signals and night vision up to 1 y, paving the way for clinical trials in patients.
Keyphrases
- gene therapy
- induced apoptosis
- end stage renal disease
- clinical trial
- chronic kidney disease
- ejection fraction
- cell cycle arrest
- peritoneal dialysis
- oxidative stress
- cancer therapy
- prognostic factors
- bipolar disorder
- diabetic retinopathy
- signaling pathway
- mass spectrometry
- dna methylation
- drug delivery
- genome wide
- mesenchymal stem cells