1. Vectors with transcytosis activity and low preexisting immunity in humans: Two novel non-primate AAV capsids were examined for tropism and transcytosis activity in wild type mice after intravitreal and subretinal injection. Neither vector showed transcytosis activity. Reporter vectors using both capsids transduced RPE and photoreceptors when administered subretinally. One of the capsids appeared Muller cell-specific when administered intravitreally. This vector may be useful in the clinic and as a research tool. Both capsids had very low human preexisting immunity. 2. Three switch mechanisms have been investigated and 2 have been eliminated. The third is being optimized. 3. Preclinical studies for a retinoschisis clinical trial: Clinical vector optimization has been completed. A manuscript regarding the vector genome design has been published (see below) and another regarding capsid type selection is about to be submitted. A pre-IND meeting with the FDA took place in February. We are currently evaluating the immune response to vector after intravitreal injection and will develop a transient immune suppression protocol if necessary. GLP vector for the toxicity study has been produced in collaboration with Fraser Wright of Children's Hospital of Philadelphia and a toxicity study has been designed. 4. Improved AMD therapeutics: 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 are currently being tested in an animal model of diabetic retinopathy. These studies are on-going. A new project examining the role that PDGF-C plays in the neovascular response has been initiated with Dr. Xuri Li of the National Eye Institute. Vector has been made and we are waiting for the results of animal studies. 5. 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. A claim that AAV type 5 vectors could package intact vector genomes in the 8-9kb range was tested and shown to be incorrect. A manuscript regarding our findings was written and is currently under review.
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