Drug repurposing involves exploring new therapeutic uses for drugs already approved by regulatory bodies. Not only does this strategy reduce drug development costs and timelines, but it can also be life-saving for patients in need of urgent help. A recent study led by scientists at UC San Francisco and Gladstone Institutes shows just how powerful drug repurposing can be. The study identified existing cancer drugs that could reverse the changes that occur in the brain during Alzheimer’s disease (AD), potentially slowing or even reversing the disease. Read on for more context on the study, published in Cell, which involved PS19 x 5xFAD mice, a double transgenic model of Alzheimer’s disease.
Identifying Versatile Cancer Drugs via Gene Expression
Alzheimer’s disease is a destructive force, causing an irreversible decline in cognition and memory, but despite decades of research and millions in annual research funds, the AD drug development pipeline remains frustratingly limited. This is due in part to the disease’s multifactorial pathophysiology. AD involves multiple genetic pathways and protein alterations, making the disease difficult to treat effectively with a single drug. However, through a rigorous gene expression comparison protocol, the study mentioned above identified two cancer medications that could treat the most common form of dementia.
Researchers Pull from Existing Gene Expression Signature Data
The UC San Francisco-Gladstone researchers sought to compare the gene expression signatures of AD with the signatures elicited by 1,300 approved drugs. To begin, the team used publicly available data from three studies of the AD brain. These studies each measured single-cell gene expression in AD and non-AD brain cells, thereby producing gene expression signatures for AD in both neurons and glia.
Next, the researchers compared these signatures with those found in the Connectivity Map. This public database shows the effects of drugs on gene expression in human cells. The team sought drugs capable of reversing the AD gene expression signature in different cell types, including neurons and glia, both of which are damaged by AD pathology. Ultimately, 25 drugs were found to reverse the signature in numerous cell types in the brain; however, only 10 had been approved by the United States Food and Drug Administration (FDA) for use in humans. As the study was based in the U.S., FDA-approved drugs were a necessity.
Identifying Cancer Drugs with AD Treatment Potential
The researchers then analyzed millions of electronic medical records to determine the impact of the approved drugs. From their initial list of 10 approved drugs, they identified several drugs that appeared to reduce the chances of Alzheimer’s disease in human subjects. They chose two cancer drugs out of the top drug candidates for laboratory testing: letrozole, an aromatase inhibitor usually used to treat breast cancer, and irinotecan, a topoisomerase inhibitor usually used to treat colon and lung cancer.
The team predicted that the drugs would each remedy AD in specific cell types. “We prioritized letrozole for its predicted reversal effects in excitatory and inhibitory neurons,” wrote the researchers in the final study text, adding that they selected irinotecan for its effects on the “glial-centric cluster,” a group of interconnected glial cells that influence brain function. “Therefore, a combination of letrozole and irinotecan potentially targets five cell types in AD,” the team wrote.
Evaluating Cancer Drugs Using PS19 x 5xFAD Mice
The team used PS19 x 5xFAD mice to test their theory. This mouse model represents an aggressive form of Alzheimer’s disease with multiple disease-related mutations. The 5xFAD line features mutations that lead to aggressive amyloid plaque deposition and cognitive deficits; the PS19 line expresses tau pathology and neurofibrillary tangles similar to those seen in human AD and tauopathies. By crossbreeding these lines, scientists are able to create a model that represents the complex neuropathology of AD, including amyloid plaques and tau tangles.
Combining the two cancer drugs had startling effects on the mice. First, the drugs effectively unreversed the AD gene expression signatures in both neurons and glia. The drugs also reduced the formation of toxic proteins, in turn reducing overall brain degeneration. Perhaps most importantly, the drug cocktail “significantly improved” memory function in some mice.
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The team wrote that this study’s results underscore the power of “multi-cell-type network-correction therapies in effectively treating AD.” AD is a profoundly complex disease; however, as Marina Sirota, Ph.D., co-senior author of the paper, noted, this multi-drug approach could be “swiftly translated into a real solution for millions of patients with Alzheimer’s.”
To study Alzheimer’s disease, Scantox Neuro offers several in vitro and in vivo models facilitating amyloid plaque and tau pathology. In vitro models range from Aβ-induced toxicology, Aβ peptide formation, and determination of Aβ aggregates to tau hyperphosphorylation, tau uptake and seeding, and tau aggregation. In vivo models include the above-mentioned 5xFAD and PS19 mouse models and several other murine APP and tau models. Models can be treated with your drug and evaluated for cognitive deficits and brain pathology by various behavioral, biochemical, and histological methods, respectively.
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