Mechanisms of Neurodegeneration and CNS therapy in Lysosomal Storage Disorders

Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal storage dysfunction. Loss of lysosomal function is associated with severe neurodegeneration, which is the prominent pathological hallmark of LSDs. One of our major goals is to elucidate how lysosomal dysfunction may specifically affect neuronal function and viability, thus allowing us to determine the neuropathological phenotype observed in LSDs. In our lab we investigate the functionality of post-Golgi membrane trafficking pathways with particular emphasis on synaptic vesicle recycling in neurons of neurodegenerative LSDs. Specifically, we want to determine whether a mechanistic relationship exists among the functionality of these trafficking pathways, the lysosomal dysfunction and LSD neuropathology. Our second research line allows us to design and test minimally invasive therapeutic approaches, which efficiently treat neuropathology in LSDs. The purpose of this is to enhance protein secretion from liver and allow efficient cross of the blood-brain barrier (BBB) to target the brain after intravascular administration of a viral vector containing the gene encoding the engineered protein. Adeno-associated virus (AAV) vectors with high tropism to the liver are used as vehicles to systemically target the liver and transform it into a factory organ for the modified enzyme. However, for further clinical applications the modified enzymes may also be directly supplied intravenously as recombinant proteins (enzyme replacement therapy). The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.