345-LB: Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): A New Therapeutic Target for Wolfram Syndrome

Endoplasmic reticulum (ER) stress is an emerging target for human chronic disorders, including β cell death in type 1 and type 2 diabetes, as well as neurodegenerative diseases. However, there is currently no treatment for preventing ER stress-mediated cell death due to its complex nature. Our strategy for overcoming this challenge is to focus on a rare monogenic disease, Wolfram syndrome. Wolfram syndrome is a rare genetic disease characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, diabetes insipidus, impaired hearing and neurodegeneration. As this syndrome is caused by the loss-of-function of the WFS1 gene which is involved in ER calcium homeostasis and ER stress-mediated cell death, it is ideal for testing potential new treatments targeting the ER. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a trophic factor whose expression and secretion is enhanced by ER stress and ER calcium depletion. It has been demonstrated that MANF plays a critical role in the survival of ER stressed β cells and neurons, raising the possibility that MANF can be beneficial for patients suffering from ER stress-related disorders. In this study, we show that treatment with recombinant MANF peptide in cell models of Wolfram syndrome suppresses the caspase 3/7 activation and terminal ER stress markers, including C/EBP homologous protein (Chop) and Tribbles 3 (Trb3), and activates the mTOR/S6K signaling pathway. Furthermore, the proliferation of β cells in a WS mouse model is activated by recombinant MANF peptide treatment and adeno-associated virus induced MANF overexpression. Our results indicate that molecular pathways regulated by MANF are promising drug targets for ER stress-related disorders, including β cell death in diabetes and Wolfram syndrome.