Unique Repurposing Approach Identifies Potential Alzheimer’s Disease Drug

November 16, 2021 | Trials for Alzheimer’s disease (AD) drugs have repeatedly failed with billions of dollars invested. Drug repurposing has also been tried before and mostly has not worked—but the problem may have been in the approach, says Yadong Huang, M.D., Ph.D., founder of the Gladstone Center for Translational Advancement in San Francisco that specializes in repurposing FDA-approved drugs for new uses.

His multidisciplinary model, described in a recent article in Nature Aging (DOI: 10.1038/s43587-021-00122-7), combines drug repurposing with precision medicine, network-based drug targeting, induced pluripotent stem cell (iPSC) technology, and real-world data analysis. More promising results can be expected moving forward on AD studies adopting the five-pronged approach, Huang says.

In the paper, he makes a strong case for repurposing bumetanide, a four-decade-old diuretic drug, to treat and perhaps even prevent AD driven by variation in the apolipoprotein E4 (APOE4) gene with multiple converging lines of evidence. If proven out in clinical trials, the implications are massive.

Among people with Alzheimer’s disease, between 10% and 15% carry a double copy of the APOE4 variation, the group his drug repurposing study linked to cognitive benefit from taking bumetanide, says Huang. That equates to about 1 million patients in the U.S. alone, and roughly 10 million worldwide.

The in-silico analysis additionally suggests that the drug, costing as little as $15 for a 30-day supply, might work more broadly against other AD patient subgroups, he adds. An analysis of the electronic medical records (EMR) of more than five million individuals over the age of 65 in the U.S. found that those taking bumetanide had between a 35% and 75% decreased possibility of being diagnosed with AD. The control group were people taking any other diuretic drug for their hypertension or edema. 

Based on these study findings, Huang and his colleagues now plan to work with multiple medical centers to move bumetanide toward human clinical trials for treating AD, starting with APOE4 carriers. Until bumetanide’s efficacy is proven for this new use, they are urging doctors not to prescribe it off-label, he notes.

The risk of dehydration in the elderly is a big concern in repurposing a diuretic as an Alzheimer’s drug. “That’s why clinical trials will most likely try different doses to see how low we can go to still show the efficacy,” says Huang. 

Making a new drug takes about 12 years and, according to a 2020 analysis published in JAMA (DOI: 10.1001/jama.2020.1166), costs about $1 billion. Other recent estimates have variably put the figure somewhere between $314 million and $2.8 billion.

The needed research and development investment required is unquestionably huge, says Huang, and the main rationale for drug repurposing efforts. The pandemic has led to a rush to repurpose existing drugs to treat COVID-19, but the success stories up to now have primarily been around the treatment of cancer.  

When he launched the Gladstone Center in 2017, it occurred to Huang that the approach also made a lot of sense for AD. He has spent more than 30 years studying APOE4—the strongest risk factor gene for AD (60%-75% of all patients have at least one copy of the variation versus 20%-25% in the general population)—and come to recognize that the cellular mechanisms underlying the cognitive deficits may differ across the broader patient population.

If true, that means different drugs are needed to treat those various gene expression patterns in subpopulations of AD, says Huang. Drug repurposing might therefore be paired with precision medicine. The network approach to drug development, targeting the whole genome expression profile of AD across different patient subpopulations, also seems to be a natural fit for the highly heterogenous disorder.

Using a publicly available database of 213 brain samples from people with and without AD, researchers compared the gene expression profiles of those carrying two copies of APOE3, two copies of APOE4, and one copy of each and saw “quite striking” differences, says Huang. Scarcely 6% of gene alterations were shared across all three groups.

Next, they queried the APOE4 signatures of AD against a Connectivity Map database containing transcriptomic perturbations of more than 1,300 drugs, to identify those shown to “flip” those gene expression alterations in a cancer cell line, he says. The top five drugs active against APOE4/4 AD were ranked and, after reviewing the literature, bumetanide was identified as the top contender. 

Bumetanide reduces extra fluid in the body caused by heart failure, liver disease, and kidney disease. It is known to work by changing how cells absorb sodium and chloride—both important not only for maintaining appropriate levels of water throughout the body, but also for electrical signaling of neurons in the brain, says Huang. 

The diuretic was subsequently tested in mouse models of APOE4 AD both with and without amyloid β (Aβ) accumulation (a major pathological sign of Alzheimer’s disease in the brain) and was shown to “completely reverse” the abnormal brain network activity that could be responsible for disease-associated cognitive deficits, says Huang. Strikingly, in the Aβ precursor protein model, bumetanide decreased the number of amyloid plaques and neuronal plasticity returned to normal.

In an effort toward extending this work in humans, the research team then reprogrammed skin cells from patients with the APOE4/4 signature into induced pluripotent stem cells (iPSC) and evolved them into brain cells in culture, he explains. Those cells were then treated with bumetanide, which again flipped many of the APOE4/4 AD signature gene expressions back to a normal state.

Analysis of the EMR data from the University of California San Francisco and Mount Sinai Health System further suggested that bumetanide provides a protective effect against AD in the elderly.

Forthcoming clinical trials will begin by looking at the drug as a treatment for diagnosed cases of mild cognitive impairment and AD in patients carrying a double copy of the APOE4 genetic variant, he says. At least one study arm will likely include those with only one copy to see if the effects of the drug might also prove useful for the APOE3/4 patient group. If so, that could easily enlarge the population impact of bumetanide to 60% of all cases of AD.

Given that the safety profile of bumetanide is well known, clinical studies could be completed within two years, Huang says. Equally notable is that his drug repurposing approach—done in a completely unbiased way with no hypothesizing—also took only two years to get from concept to identification of a candidate drug.

The tactic may well be useful for many age-related or otherwise complex diseases, he adds. To that end, the Gladstone Center hopes to build a new drug library over the next few years inclusive of the more than 12,000 drugs that have passed phase 1 safety testing. It is also endeavoring to create a database containing all the major brain cell types (excitatory neurons, inhibitory neurons, microglia, and astrocytes) developed from iPSC that might be needed for drug repurposing work focused on the diseases occurring in the central nervous system.

How far any drug repurposing agenda goes is heavily dependent on government grants and charitable donations, Huang points out. Pharmaceutical companies aren’t financially incentivized to invest in drugs whose patents have expired.

Up until very recently there was no “clearly effective approach” for how best to do drug repurposing for complex diseases, such as Alzheimer’s disease, he says, which may help explain why results of such efforts have been largely underwhelming. “Our study highlights the power of combining computational drug repurposing with precision medicine, as well as the usefulness of leveraging existing sets of experimental and real-world data for rapid preliminary validation.”