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31	Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses Golebiowski, Diane L. 01 September 2016 (has links) GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose. AAV Gene therapy CNS Tay-sachs disease Sandhoff disease GM2 gangliosidosis Disease Modeling Enzymes and Coenzymes Molecular Biology Nervous System Diseases Other Neuroscience and Neurobiology Pharmacology Toxicology Translational Medical Research
32	Oceanographic Considerations for the Management and Protection of Surfing Breaks Scarfe, Bradley Edward January 2008 (has links) Although the physical characteristics of surfing breaks are well described in the literature, there is little specific research on surfing and coastal management. Such research is required because coastal engineering has had significant impacts to surfing breaks, both positive and negative. Strategic planning and environmental impact assessment methods, a central tenet of integrated coastal zone management (ICZM), are recommended by this thesis to maximise surfing amenities. The research reported here identifies key oceanographic considerations required for ICZM around surfing breaks including: surfing wave parameters; surfing break components; relationship between surfer skill, surfing manoeuvre type and wave parameters; wind effects on waves; currents; geomorphic surfing break categorisation; beach-state and morphology; and offshore wave transformations. Key coastal activities that can have impacts to surfing breaks are identified. Environmental data types to consider during coastal studies around surfing breaks are presented and geographic information systems (GIS) are used to manage and interpret such information. To monitor surfing breaks, a shallow water multibeam echo sounding system was utilised and a RTK GPS water level correction and hydrographic GIS methodology developed. Including surfing in coastal management requires coastal engineering solutions that incorporate surfing. As an example, the efficacy of the artificial surfing reef (ASR) at Mount Maunganui, New Zealand, was evaluated. GIS, multibeam echo soundings, oceanographic measurements, photography, and wave modelling were all applied to monitor sea floor morphology around the reef. Results showed that the beach-state has more cellular circulation since the reef was installed, and a groin effect on the offshore bar was caused by the structure within the monitoring period, trapping sediment updrift and eroding sediment downdrift. No identifiable shoreline salient was observed. Landward of the reef, a scour hole ~3 times the surface area of the reef has formed. The current literature on ASRs has primarily focused on reef shape and its role in creating surfing waves. However, this study suggests that impacts to the offshore bar, beach-state, scour hole and surf zone hydrodynamics should all be included in future surfing reef designs. More real world reef studies, including ongoing monitoring of existing surfing reefs are required to validate theoretical concepts in the published literature. Aramoana Beach Dunedin (New Zealand) ArcGIS ArcSDE artificial surfing reef backscatter Baseline Data Collection bathymetry bathymetric surveying beach morphodynamics beach-state and morphology breaking wave height coastal engineering coastal environment coastal management coastal monitoring coastal processes coastal structures currents economic value EIA environmental data management environmental impact assessment geographic information systems geoid geomorphic surfing break categorisation GIS groin hydrodynamic modelling hydrographic surveying hydrography ICZM incline plane modelling integrated coastal zone management Main Beach Mount Maunganui (New Zealand) Manu Bay Boat Ramp Raglan (New Zealand) measuring water levels morphological coupling multibeam echo soundings oceanography offshore wave transformations Palm Beach Reefs Gold Coast (Australia) RTK GPS salient surf zone hydrodynamics surfing break components surfing reefs surfing tourism surfing wave climate surfing wave parameters Tay Street Mount Maunganui (New Zealand) wave breaking intensity wave climate wave focusing wave modelling wave peel angle wave section length wind effects on waves

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Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses

Oceanographic Considerations for the Management and Protection of Surfing Breaks