TY - JOUR
T1 - A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome
AU - Mahadevan, Jana
AU - Morikawa, Shuntaro
AU - Yagi, Takuya
AU - Abreu, Damien
AU - Lu, Simin
AU - Kanekura, Kohsuke
AU - Brown, Cris M.
AU - Urano, Fumihiko
N1 - Funding Information:
Conflict of interest FU and KK are inventors of US Patent 9,891,231 B2 entitled “SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS.” FU and SL are inventors of US 10,441,574, B2 entitled “TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS.” FU received research funding from Eli Lilly, Ono Pharmaceuticals, and Amarantus BioScience for the development of MANF-based regenerative therapy for Wolfram syndrome, optic nerve atrophy, and diabetes. FU received chemical compounds from Amylyx Pharmaceuticals, Mitochon Pharmaceuticals, Aetas Pharma, and National Center for Advancing Translational Sciences for the development of small molecule-based therapies for ER stress-related disorders, including Wolfram syndrome. The other authors declare no conflict of interest.
Funding Information:
Acknowledgements This work was partly supported by grants from Ono Pharmaceutical Co Ltd, the National Institute of Diabetes Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) (DK112921 and DK020579), the National Center for Advancing Translational Sciences (NCATS) of the NIH (TR002065 and TR000448) and philanthropic supports from the Silberman Fund, the Ellie White Foundation for the Rare Genetic Disorders, the Snow Foundation, the Unravel Wolfram Syndrome Fund, the Stowe Fund, the Eye Hope Foundation, the Feiock Fund, the Team Alejandro, and the Team Ian to FU. Research reported in this publication was also supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the NCATS of the NIH and the Washington University Diabetes Research Center supported by the NIDDK of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. SM was supported by Manpei Suzuki Diabetes Foundation and JSPS Overseas Research Fellowships. DA was supported by the NIH training grant (F30DK111070). The authors thank all the members of the Washington University Wolfram Syndrome Study and Research Clinic for their support (https://wolframsyndrome. dom.wustl.edu) and all the participants in the Wolfram syndrome
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome.
AB - Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome.
UR - http://www.scopus.com/inward/record.url?scp=85085133614&partnerID=8YFLogxK
U2 - 10.1038/s41374-020-0436-1
DO - 10.1038/s41374-020-0436-1
M3 - Article
C2 - 32366942
AN - SCOPUS:85085133614
VL - 100
SP - 1197
EP - 1207
JO - Laboratory Investigation
JF - Laboratory Investigation
SN - 0023-6837
IS - 9
ER -