. Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease. Nature Aging, 11 October 2021.

Abstract:

Taubes, A., Nova, P., Zalocusky, K.A. et al.

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  1. Taubes and colleagues identified the sulfamyl diuretic bumetanide, used to treat high blood pressure among other conditions, as a potential drug repurposing candidate for late-onset Alzheimer’s disease. Bumetanide is a plausible candidate, and previous studies have hinted that hypertension treatment could reduce the risk of developing Alzheimer’s disease and other types of dementia.

    The drug was identified using a method known as “signature mapping,” where APOE-dependent gene expression signatures of Alzheimer’s disease were integrated with drug-gene signatures from the Broad Institute’s Connectivity Map. Signature mapping basically prioritizes drugs that are predicted to “normalize” a disease signature, assuming this will alleviate disease symptoms and potentially halt onset and progression of disease.

    My lab and others have also demonstrated the utility of this approach in Alzheimer’s disease (Gerring et al., 2021). 

    The functional validation and retrospective clinical record evidence that support bumetanide in Alzheimer’s is particularly impressive. The use of APOE-knock-in mice to not only show bumetanide reverses hallmark pathological changes in Alzheimer’s disease but potentially reverses cognitive deficits is an important first step to argue for human clinical trials.

    The replication of the (predicted) Connectivity Map signatures using induced pluripotent stem cell-derived neurons is an important validation of the signature mapping approach. This is particularly important because, as the authors point out, the Connectivity Map signatures are derived from cancer lines, rather than neuronal or glial cell lines. Many have argued the connectivity map is inappropriate for brain-related diseases. These results suggest otherwise. However, I believe the development of a connectivity map for brain-cell types is critical for the discovery of new drug candidates for neurological and psychiatric diseases.

    Finally, the use of electronic medical records, while fraught with the limitations of retrospective data analysis (i.e., causality cannot be established due to unobserved confounders), provided additional support for the use of bumetanide in Alzheimer’s disease. The replication of results across two independent medical record databases, combined with efforts to control for hypertension, improves the validity of these results.

    Overall, it’s great to see such a comprehensive drug-repurposing study. The authors provide a compelling case for bumetanide in Alzheimer’s disease in addition to an experimental validation of sorts for the use of “signature mapping” in other brain-related diseases.

    References:

    . Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease. Neurol Genet. 2021 Oct;7(5):e622. Epub 2021 Sep 9 PubMed.

    View all comments by Zac Gerring
  2. This study provides a comprehensive and impressive roadmap to develop an evidence base for bumetanide, a loop diuretic, as a repurposed candidate drug for Alzheimer’s disease. Their treatment target was the reversal of characterized ApoE4-dependent transcriptomic signatures. They incorporated the publicly available databases for ApoE genotype-dependent transcriptomic signatures in human brain, and high-throughput screening of more than 1,300 drugs, to see which could reverse these signatures, with bumetanide emerging as the top candidate.

    Taking this treatment into ApoE knock-in mice, with and without Aβ accumulation, the authors demonstrate how bumetanide can reverse electrophysiological, cognitive, and behavioral deficits in preclinical animal models and in pluripotent stem cell-derived neurons. They extended their studies with pharmaco-epidemiological investigations of bumetanide from the UCSF and Mount Sinai health systems electron health record databases to identify lower AD prevalence in individuals over age 65 on bumetanide than in those not so treated.

    Parenthetically, this medication has previously attracted attention for the treatment of brain diseases, including neonatal seizures and autism spectrum, with some putative GABAergic inhibitory properties. It would be very helpful to know how long it took to complete all the different pieces of this research plan and bring it to its current status.

    The authors conclude that these studies support bumetanide as a promising clinical trials candidate for AD. This prospect raises important questions for its future clinical development plan, including the dose selection, or range of doses to be tested, the pharmacodynamic endpoints that will be used in these clinical trials to judge the sufficiency of dose, the strategy for selecting the disease stage to test it in, and the detailed design considerations of the first clinical trials. Whether bumetanide, a potent diuretic with the potential for considerable metabolic side effects in older persons, is going to be viable will likely come down to dose and tolerability.

    All these considerations follow the impressive contribution of Taubes et al., who have provided an excellent roadmap for a repurposing drug that pursues a target-specific ApoE4 approach, whether or not it is bumetanide that eventually fulfills the clinical promise. 

    View all comments by Howard Feldman
  3. This is an interesting and well-done paper. Its strengths include the use of multiple converging lines of evidence, such as big data confirmed in mice and iPSCs, an effect reflected in patient electronic medical records (i.e., reduced AD), and a focus on APOE, an important and neglected therapeutic target.

    The study also raises questions. For example, bumetanide worked as well in animals without amyloid as in those with amyloid; so this mechanism may not be specific to AD. The pathways involved—morphine addiction, GABA-ergic pathways, circadian entrainment—are not usually implicated in AD.

    Bumetanide is a very strong diuretic that can produce dehydration and electrolyte imbalance. It would be difficult to use in older patients with AD. It may be possible to re-re-engineer the molecule if these pathways are confirmed to be important.

    The confirmation of the cell-based and mouse effects in the eHR is encouraging with the following caveats: AD was reduced in patients who had congestive heart failure or other conditions that may not be present in many AD patients, and the exposures in those patients may have been much longer than most trials would allow.

    Overall, the observations in this study may apply more broadly than just to AD.

    View all comments by Jeffrey Cummings

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