Purpose To characterize the intraocular immune cell infiltrate induced by intravitreal adeno-associated virus (AAV) gene therapy. Methods AAV vectors carrying plasmids expressing green fluorescent protein under the control of PR2.1 were injected intravitreally into AAV naive and AAV primed C57Bl/6 mice. Clinical inflammation was assessed using optical coherence tomography. Intraocular immune cell populations were identified and quantified by flow cytometry on days 1, 7, and 29 after intravitreal injection and compared with sham and fellow eye controls. Results Optical coherence tomography inflammation score and total CD45+ cell number were significantly higher in AAV injected eyes compared to uninjected fellow eye and sham injected controls. Clinically apparent inflammation (vitritis on optical coherence tomography) and cellular inflammation (CD45+ cell number) was significantly increased in AAV injected eyes and peaked around day 7. Vitritis resolved by day 29, but cellular inflammation persisted through day 29. On day 1, neutrophils and activated monocytes were the dominant cell populations in all AAV injected eyes. On day 7, eyes of AAV exposed animals had significantly more dendritic cells and T cells than eyes of AAV naive animals. By day 29, CD8– T cells were the dominant CD45+ cell population in AAV injected eyes. Conclusions Intravitreal AAV injection in mice generates clinically evident inflammation that is mild and seems to resolve spontaneously. However, the total number of intraocular CD45+ cells, particularly T cells, remain elevated. Both innate and adaptive immune cells respond to intravitreal AAV regardless of prior immune status, but the adaptive response is delayed in AAV naive eyes.
Here we present evidence implicating disrupted RNA splicing as a potential cause of inherited tritan color vision. Initially we tested 51 subjects for color vision deficiencies. One made significant tritan errors; the others were classified as normal trichromats. The putative tritan subject was the only one of the 51 subjects found to be heterozygous for an OPN1SW gene mutation that disrupts RNA splicing in an in vitro assay. In order to gather further support for the role of the splicing mutation in tritan color vision, the putative tritan subject’s mother and sister were examined. They also made tritan errors and had the same OPN1SW gene mutation.
Neurologic Diseases (iNcluDiNg ophthalmic aND auDitory Diseases) i called ProSavin®. OXB-102 is an improved version of ProSavin® that expresses the same enzymes but with an increased DA production per genetically modified cell. In non-clinical studies the efficacy of a full-strength and a 1/5th dose of OXB-102 has been compared to the efficacy of full-strength ProSavin® in the 'gold standard' MPTP NHP model of PD; a vector that does not express any genes was used as a negative control. The longitudinal follow-up consisted of recording clinical rating scores and video-based quantification of locomotor activity before and after vector administration. The full-strength and the 1/5th dose of OXB-102 were as efficacious as the full-strength dose of ProSavin®, whereas the control-treated macaques maintained a significant PD phenotype, indicating improved dopamine production from OXB-102. Positron emission tomography (PET) was also carried out at baseline and at 3 and 6 months following vector administration using 18F-FMT, a presynaptic biomarker that acts as a substrate of AADC. There was a significant increase in the FMT signal in both of the OXB-102 treatment groups that was greater than in the ProSavin® treated animals whilst there was no significant change in the FMT signal in the control treatment group. Results from a 6-month toxicology and biodistribution study in the NHP indicate that the OXB-102 vector is safe and well tolerated following stereotactic administration into the putamen and the vector does not significantly spread beyond the site of administration GMP manufacture of OXB-102 for a planned clinical trial in PD patients is currently in progress.
The SOAR telescope will begin science operations in 2Q 2003. From the outset, astronomers at all U.S. research universities will be able to use it remotely, avoiding 24+ hrs of travel, and allowing half-nights to be scheduled to enhance scientific return. Most SOAR telescope systems, detector array controllers, and instruments will operate under LabVIEW control. LabVIEW enables efficient intercommunication between modules executing on dispersed computers, and is operating-system independent. We have developed LabVIEW modules for remote observing that minimize bandwidth to the shared LAN atop Cerro Pachón. These include control of a Polycom videoconferencing unit, export of instrument control GUI's and telescope telemetry to tactical displays, and a browser that first compresses an image in Chile by a factor of 256:1 from FITS to JPEG2000 and then sends it to the remote astronomer. Wherever the user settles the cursor, a region-of-interest window of lossless compressed data is downloaded for full fidelity. As an example of a dedicated facility, we show layout and hardware costs of the Remote Observing Center at UNC, where instruments on SOAR, SALT, and other telescopes available to UNC-CH astronomers will be operated.
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