Targeting the lysosome-mitochondria axis in neurodegenerative lysosomal storage diseases - Lessons from telomerase immortalization

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We have identified a link between telomerase immortalization and correction of the NPC1 lipid storage phenotype. Furthermore, we have recently identified the stress transcription factor NRF1 as one of the genes induced by telomerase, especially in cells that are already under stress such as Niemann-Pick C disease cells characterized by lysosomal cholesterol storage. These results are particularly exciting since among many cellular functions assigned to NRF1 it was recently shown to be a central player in cellular cholesterol homeostasis. We subsequently determined that ectopic expression of NRF1 alone could correct the NPC1 cholesterol storage phenotype suggesting that NRF1 provides a link between mitochondria and lysosome function and under stress (disease) conditions NRF1 could normalize their function. Thus, we have identified a transcription factor that is a novel target for NPC1 disease and potentially for many other lysosomal storage disorders. It is known however, that transcription factors are notoriously difficult to drug and present unique challenges due to their tight and often intricate regulation. For these reasons we were excited to identify two unique methods for activating NRF1 in target, disease cells. First, using a novel transcriptional activation assay we have developed we have identified a group of FDA-approved calcium channel inhibitors that are very potent activators of NRF1. Second, we have identified an interesting property of telomerase immortalized NPC1 cells; they secreted exosomes that contain high levels of active NRF1 that are capable of transferring this trasncription factor to target cells. By targeting NRF1, the goals of this proposal are first to validate its therapeutic potential to treat NPC1 disease and thus address a great-unmet need. Second, to evaluate their therapeutic effectiveness in vivo using an animal model of NPC1 disease. The success of these studies will provide preclinical validation of this novel approach and provide the rationale for further therapeutic development.