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Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype

EMBO Mol Med. 2021 Aug 19:e13742. doi: 10.15252/emmm.202013742. Epub ahead of print. PMID: 34411438.

Authors/Editors: Soldati C, Lopez-Fabuel I, Wanderlingh LG, Garcia-Macia M, Monfregola J, Esposito A, Napolitano G, Guevara-Ferrer M, Scotto Rosato A, Krogsaeter EK, Paquet D, Grimm CM, Montefusco S, Braulke T, Storch S, Mole SE, De Matteis MA, Ballabio A, Sampaio JL, McKay T, Johannes L, Bolaños JP, Medina DL.
Publication Date: 2021



Batten diseases (BDs) are a group of lysosomal storage disorders
characterized by seizure, visual loss, and cognitive and motor dete-
rioration. We discovered increased levels of globotriaosylceramide
(Gb3) in cellular and murine models of CLN3 and CLN7 diseases
and used fluorescent-conjugated bacterial toxins to label Gb3 to
develop a cell-based high content imaging (HCI) screening assay
for the repurposing of FDA-approved compounds able to reduce
this accumulation within BD cells. We found that tamoxifen
reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell
models, including neuronal progenitor cells (NPCs) from CLN7
patient-derived induced pluripotent stem cells (iPSC). Here, tamox-
ifen exerts its action through a mechanism that involves activation
of the transcription factor EB (TFEB), a master gene of lysosomal
function and autophagy. In vivo administration of tamoxifen to the
CLN7Dex2 mouse model reduced the accumulation of Gb3 and
SCMAS, decreased neuroinflammation, and improved motor coor-
dination. These data strongly suggest that tamoxifen may be a
suitable drug to treat some types of Batten disease

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