Enhancement of a novel gene therapy approach for Sandhoff disease through complimentary drug therapy

GM2 gangliosidoses is a family of severe, neurodegenerative disorders resulting from a deficiency in the β-hexosaminidase A (Hex A) enzyme. This disorder is typically caused by a mutation to either the HEXA gene, causing Tay Sachs disease, or a mutation to the HEXB gene, causing Sandhoff disease. The HEXA and HEXB genes are required to produce the α and β subunits of the Hex A enzyme respectively. Using a Sandhoff disease (SD) mouse model (Hexb-/-) we tested the potential of a low dose of systemically delivered single stranded adeno-associated virus 9 (ssAAV9) expressing human HEXB and human HEXA cDNA under the control of a single promoter through the use of a bicistronic vector design with a P2A linker to correct the neurological phenotype. Neonatal mice were injected with either this ssAAV9-HexB-P2A-HexA vector (HexB-HexA) or a vehicle solution via the superficial temporal vein. HexB-HexA treatment alone conferred an increase in survival of 56% compared to vehicle-injected controls and biochemical analysis of the brain tissue and serum revealed an increase in HexA activity and a decrease in brain GM2 ganglioside buildup. Additionally, treatments with the non-steroidal anti-inflammatory drug indomethacin (Indo), the histone deactylase inhibitor ITF2357 (ITF) and the pharmacological chaperone pyrimethamine (Pyr) were tested. The anti-inflammatory treatments of Indo and ITF conferred an increase in survival of 12% and 8% respectively while causing no alteration in the HexA activity or GM2 ganglioside buildup. Pyr had no observable effect on disease progression. Lastly HexB-HexA treatment was tested in conjunction with Indo, ITF and Pyr individually. Additive increases in survival and behavioural testing results were observed with Indo and ITF treatments while no additional benefit to HexA activity or GM2 ganglioside levels in the brain tissue was observed. This indicates the two treatments slowed the progression of the disease through a different mechanism than the reduction of the GM2 ganglioside substrate. Pyr treatment was shown to have no effect when combined with HexB-HexA treatment. This study demonstrates the potential amelioration of SD with a novel AAV9 gene therapy approach as well as helped to identify the additive potential of anti-inflammatory treatments in gene therapy of GM2 gangliosidoses.

Reform and Redesign: A Review of the Changing Role of the Public Purposes in R&D and Technology Institutes (Working Paper 17)

As the globalization of knowledge has taken hold over the past decade, and as governments around the world review their new roles in support of the production of knowledge, several factors have shaped the context in governments’ approach to public research. Arguably, none has been more affected by these pressures for reform than government scientific and technology laboratories or institutes. Often ignored in the re-shaping of national systems of innovation, these organizations play an important role in advancing national economic and social objectives. This paper, by reviewing examples of reforms underway in several countries, including Canada, France, Germany, the UK, Japan, USA and Latin America, will argue that government research and technology institutes — often historically surrogates for industrial research — are gradually re-defining their mandates to meet the new pressures of globalization as well as satisfying growing public demands for increased relevance and efficiency in responding to citizens’ and industry needs.

THE ELEMENTARY TEACHERS’ PERCEPTIONS OF MOTIVATION FOR AND THE PRINCIPAL’S INFLUENCE ON THEIR ENGAGEMENT IN SELF-DIRECTED PROFESSIONAL DEVELOPMENT

All teachers participate in self-directed professional development (PD) at some point in their careers; however, the degree to which this participation takes place varies greatly from teacher to teacher and is influenced by the leadership of the school principal. The motivation behind why teachers choose to engage in PD is an important construct. Therefore, there is a need for better understanding of the leader’s role with respect to how and why teachers engage in self-directed professional development. The purpose of the research was to explore the elementary teachers’ motivation for and the school principal’s influence on their engagement in self-directed professional development. Three research questions guided this study: 1. What motivates teachers to engage in self-directed professional development? 2. What are the conditions necessary for promoting teachers’ engagement in self-directed professional development? 3. What are teachers’ perceptions of the principal’s role in supporting, fostering, encouraging, and sustaining the professional development of teachers? A qualitative research approach was adopted for this study. Six elementary teachers from one south-eastern Ontario school board, consisting of three novice and three more experienced teachers, provided their responses to a consistent complement of 14 questions. Their responses were documented via individual interviews, transcribed verbatim, and thematically analysed. The findings suggested that, coupled with the individual motivating influences, the culture of the school was found to be a conditional dynamic that either stimulated or dissuaded participation in self-directed PD. The school principal provided an additional catalyst or deterrence via relational disposition. When teachers felt their needs for competency, relatedness, and autonomy were satisfied, the conditions necessary to motivate teachers to engage in PD were fulfilled. A principal who personified the tenets of transformational leadership served to facilitate teachers’ inclinations to take on PD. A leadership style that was collaborative and trustful and allowed for personal autonomy was a dominant foundational piece that was critical for participant participation in self-directed PD. Finally, the principals were found to positively impact school climate by partaking in PD alongside teachers and ensuring there was a shared vision of the school so that teachers could tailor PD to parallel school interests.