1. Preclinical studies for a retinoschisis clinical trial: We have evaluated 5 new retinoschisin vector and have identified one that shows good efficacy in mouse models at a 10-fold lower dose than our previous clinical candidate. We have completed a preclinical efficacy study with this vector. We also completed preclinical toxicity and biodistribution studies in rabbits examining a broad dose range. The vector was well tolerated in rabbits at scaled doses that correspond to doses that show efficacy in the retinoschisis mouse model. We are now preparing for a GLP toxicity study. 2. Retinitis Pigmentosa due to: RPGR mutation: Full length human and mouse RPGR vectors have been constructed and produced. Genetic manipulation of the intact authentic RPGR exon ORF15 (required for this construct) has not been achieved by most/all other groups Im aware of. The vectors are being evaluated in 2 animal models of RPGR mutation for preclinical efficacy studies. These 2 models are rather slow to develop pathology. Faster models are being developed. RP2: Vector has been produced and is being tested in preclinical efficacy models. 3. CEP290: Vectors have been prepared for this project and are being tested in vivo for expression and efficacy. This project has been expanded to examine several strategies for vector construction. The problem is that the CEP290 gene is 7.4 kb in length and AAV vectors can only package about 5 kb. We are evaluating lentiviral vectors and compacted DNA particles as potential alternative gene transfer vehicles. These studies are ongoing. 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. A manuscript has been submitted and is currently under review. 5. We are screening for capsids with balanced rod/cone transduction properties. These studies are ongoing.
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