Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease
Alice Taubes, Phil Nova, Kelly A Zalocusky, Idit Kosti, Mesude Bicak, Misha Y Zilberter, Yanxia Hao, Seo Yeon Yoon, Tomiko Oskotsky, Silvia Pineda, Bin Chen, Emily A Aery Jones, Krishna Choudhary, Brian Grone, Maureen E Balestra, Fayzan Chaudhry, Ishan Paranjpe, Jessica De Freitas, Nicole Koutsodendris, Nuo Chen, Celine Wang, William Chang, Alice An, Benjamin S Glicksberg, Marina Sirota, Yadong Huang, Alice Taubes, Phil Nova, Kelly A Zalocusky, Idit Kosti, Mesude Bicak, Misha Y Zilberter, Yanxia Hao, Seo Yeon Yoon, Tomiko Oskotsky, Silvia Pineda, Bin Chen, Emily A Aery Jones, Krishna Choudhary, Brian Grone, Maureen E Balestra, Fayzan Chaudhry, Ishan Paranjpe, Jessica De Freitas, Nicole Koutsodendris, Nuo Chen, Celine Wang, William Chang, Alice An, Benjamin S Glicksberg, Marina Sirota, Yadong Huang
Abstract
The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.
Conflict of interest statement
Completing Interests Statement Y. Huang is a cofounder and scientific advisory board member of E-Scape Bio, Inc., GABAeron, Inc., and Mederon Bio, LLC. M.S. is on the advisory board of Aria Pharmaceuticals. A pending patent application related to this work has been filed, on which Y. Huang, AT, MS, and PN were listed as inventors. Other authors declare no competing financial interests.
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Source: PubMed