1. Preclinical studies for a retinoschisis clinical trial: We have completed a preclinical efficacy study using a self-complementary AAV8 vector carrying a human retinoschisin expression cassette. The GLP-grade vector has been made for a toxicity study starting at September 2013. Assays of vector stability and AAV8 neutralizing antibody have been established for the upcoming toxicity study. 2. Retinitis Pigmentosa due to: RPGR mutation: We have tested the mouse and human RPGR AAV vectors in two mouse models with RPGR deficiency. Both vectors have shown efficacy in the RPGR knock-out model at 18 months post-administration. The data collection on the Rd9 mouse model is ongoing. To develope an RPGR mouse model with a faster retinal degeneration, a knock-in model has been generated. However, this model appears to be another loss-of-function model similar to the two exsiting models and displays a slow retinal degeneration. An AAV-mediated gene transfer strategy is being used to screen for gain-of-function RPGR mutants. RP2 mutation: We have made an AAV8 human RP2 vector and have tested it in an RP2-null mouse model. Cone functions were rescued at 4 months post-administration and this rescue effect lasted 18 months. Improvement of rod functions was not obvious after treatment due to the mouse model's unique degeneration kinetics in which the rod degeneration happens within 1 month of birth but stabilizes thereafter. 3. Improved therapeutics for neovascular diseases: In collaboration with Dr. Carmen Clapp of the Universidad Nacional Autonoma de Mexico, Juriquilla campus, we are examining a novel anti-angiogenic fragment of prolactin, called vasoinhibin, in the context of AAV vectors. AAV vectors encoding vasoinhibin, prolactin, and sFlt-1 (a soluble VEGF receptor fragment that acts as a competitive inhibitor) have been produced and have been tested in an animal model of diabetic retinopathy. These studies have been successful and were published. We have recently optimized the vectors by converting them into the more efficient self-complementary AAV forms. These vectors are being made and will be tested in the animal model.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Bush, Ronald A; Zeng, Yong; Colosi, Peter et al. (2016) Preclinical Dose-Escalation Study of Intravitreal AAV-RS1 Gene Therapy in a Mouse Model of X-linked Retinoschisis: Dose-Dependent Expression and Improved Retinal Structure and Function. Hum Gene Ther 27:376-89
Song, Hongman; Vijayasarathy, Camasamudram; Zeng, Yong et al. (2016) NADPH Oxidase Contributes to Photoreceptor Degeneration in Constitutively Active RAC1 Mice. Invest Ophthalmol Vis Sci 57:2864-75
Díaz-Lezama, Nundehui; Wu, Zhijian; Adán-Castro, Elva et al. (2016) Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1. Lab Invest 96:283-95
Hanke-Gogokhia, Christin; Wu, Zhijian; Gerstner, Cecilia D et al. (2016) Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors. J Biol Chem 291:7142-55
Ou, Jingxing; Vijayasarathy, Camasamudram; Ziccardi, Lucia et al. (2015) Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer. J Clin Invest 125:2891-903
Shen, F; Mao, L; Zhu, W et al. (2015) Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1. Gene Ther 22:893-900
Mookherjee, Suddhasil; Hiriyanna, Suja; Kaneshiro, Kayleigh et al. (2015) Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 (RP2)-knockout mice by gene replacement therapy. Hum Mol Genet 24:6446-58
Wu, Zhijian; Hiriyanna, Suja; Qian, Haohua et al. (2015) A long-term efficacy study of gene replacement therapy for RPGR-associated retinal degeneration. Hum Mol Genet 24:3956-70
Marangoni, Dario; Wu, Zhijian; Wiley, Henry E et al. (2014) Preclinical Safety Evaluation of a Recombinant AAV8 Vector for X-linked Retinoschisis after Intravitreal Administration in Rabbits. Hum Gene Ther Clin Dev :
Tian, Wenhong; Dong, Xiaoyan; Wu, Xiaobing et al. (2013) High-throughput functional microRNA profiling using recombinant AAV-based microRNA sensor arrays. Methods Mol Biol 1039:261-77

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