Repurposing drugs to treat Alzheimer’s Disease

LSP investigators working with the Massachusetts Alzheimer's Disease Research Center at the MGH are developing new approaches to treat Alzheimer's Disease based on the hypothesis that the disease has multiple distinct etiologies, some involving degeneration-associated chronic inflammation.

As populations age, Alzheimer's disease poses a rapidly increasing burden for healthcare systems, and the disease is a tragedy for the individuals and families involved. Discovering new drugs for neurodegenerative diseases is challenging because their cause is poorly understood, they progress relatively slowly, and end-stage disease – when symptoms are most obvious - remains difficult to treat. For these reasons, we are pursuing multiple approaches to repurposing FDA-approved drugs for other indications. To investigate repurposing opportunities, we are mining large-scale clinical databases (in collaboration with colleagues in the UK) and developing pre-clinical models of neurodegeneration. The machine learning algorithm DRIAD (Drug Repurposing In Alzheimer's Disease), for example, uses profiling data from human neural cell cultures treated with existing compounds to generate ranked lists of possible repurposing candidates. Some of these drug candidates have advanced to early-stage clinical trials. Our long-term goal is to use repurposed drugs to better-understand disease mechanisms and guide the development of more effective molecules that are tailored to specific types of Alzheimer's Disease.

Rodriguez S, Sahin A, Schrank BR, Al-Lawati H, Costantino I, Benz E, Fard D, Albers AD, Cao L, Gomez AC, Evans K, Ratti E, Cudkowicz M, Frosch MP, Talkowski M, Sorger PK, Hyman BT, Albers MW. Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss. Sci Transl Med. 2021 Jul 7;13(601):eaaz4699. PMCID: PMC8779652.

Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA, Evans K, Zhou G, Johnson NT, Hyman B, Sorger PK, Albers MW, Sokolov A. Machine Learning Identifies Novel Candidates for Drug Repurposing in Alzheimer’s Disease. Nat Commun. Cold Spring Harbor Laboratory; 2020 May 16;2020.05.15.098749. PMCID: PMC7884393.

Song Y, Subramanian K, Berberich MJ, Rodriguez S, Latorre IJ, Luria CM, Everley R, Albers MW, Mitchison TJ, Sorger PK. A dynamic view of the proteomic landscape during differentiation of ReNcell VM cells, an immortalized human neural progenitor line. Sci Data. 2019 Feb 19;6:190016. PMCID: PMC6380223.

Charpignon ML, Vakulenko-Lagun B, Zheng B, Magdamo C, Su B, Evans K, Rodriguez S, Sokolov A, Boswell S, Sheu YH, Somai M, Middleton L, Hyman BT, Betensky RA, Finkelstein SN, Welsch RE, Tzoulaki I, Blacker D, Das S, Albers MW. Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia. Nat Commun. 2022 Dec 10;13(1):7652. PMCID: PMC9741618

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