1. Preclinical studies for an X-linked retinoschisis gene therapy 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. A toxicity study is ongoing and is anticipated to finish in December 2014. 2. Preclinical gene therapy studies for retinitis pigmentosa due to RPGR or RP2 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 18-24 months post-administration. The data collection on the Rd9 mouse model is ongoing. To develop an RPGR mouse model with a faster retinal degeneration, we have generated RPGR knock-out model with an albino background. Characterization of this new disease model is ongoing. 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. Gene therapy for Leber Congenital Amaurosis due to CEP290 mutation Since the size of CEP290 cDNA exceeds the packaging limit of AAV vector, we are seeking several approaches including the use of dual-vector and functional subunit of CEP290 to deliver the therapeutic genes. We have made a series of AAV vectors and have tested them on a mouse model of the disease. We recently identified one vector that is capable of preserving the retinal function and structure of the mouse model. 4. 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 have been made and are being tested in the animal model.
Showing the most recent 10 out of 30 publications
