UVA’s Bradley D. Gelfand, Ph.D., and collaborators have found early evidence that the drug fluoxetine may be effective against atrophic (or “dry”) age-related macular degeneration, a condition that affects nearly 200 million people worldwide.
The drug has shown promise in the scientists’ lab tests and animal models, and the researchers bolstered by their results by examining two huge insurance databases encompassing more than 100 million Americans. That analysis concluded that patients taking fluoxetine were less likely to develop atrophic macular degeneration (AMD).
Based on their findings, the researchers are urging clinical trials to test the drug in patients with AMD. If successful, they believe the drug could be administered either orally or via a long-lasting implant in the eye.
“These findings are an exciting example of the promise of drug repurposing, using existing medicines in new and unexpected ways,” said Gelfand, of UVA’s Center for Advanced Vision Science. “Ultimately, the best way to test whether fluoxetine benefits macular degeneration is to run a prospective clinical trial.”
The researchers believe fluoxetine works against AMD by binding with a particular agent of the immune system known as an inflammasome. This inflammasome, NLRP3-ASC, triggers the breakdown of the pigmented layer of the eye’s retina.
After conducting extensive bench research, Gelfand and his team tested fluoxetine and eight other depression drugs in lab mice to see what effect, if any, the drugs would have in a model of AMD. Fluoxetine slowed the progression of the disease, but the others did not, the scientists found.
Encouraged by their findings, the researchers looked at fluoxetine use among patients over age 50 in two enormous insurance databases. People taking the drug had a “significantly” slower rate of developing dry AMD, the researchers report in a new scientific paper outlining their findings.
They note that their approach, combining bench research with big-data analysis, could potentially facilitate the repurposing of existing drugs for many conditions, speeding new treatments to patients.
“Traditional approaches to drug development can be expensive and time-consuming: On average, a new FDA-approved drug takes 10-12 years and costs $2.8 billion (present-day dollars) to develop,” the researchers wrote.
“Our identification of the unrecognized therapeutic activity of an existing FDA-approved drug using big data mining, coupled with demonstrating its efficacy in a disease-relevant model, could greatly accelerate and reduce the cost of drug development.”
Gelfand was involved earlier this year in using a similar approach to determine that HIV drugs known as nucleoside reverse transcriptase inhibitors, or NRTIs, may be useful against dry macular degeneration as well.
“While we have had a great deal of success with the approach of using real-world patient data, we may have only begun to scratch the surface of finding new uses for old drugs,” said Gelfand, of UVA’s departments of ophthalmology and biomedical engineering. “It is tempting to think about all the untapped therapeutic potential of medicines sitting on pharmacy shelves.”
The researchers have published their findings in the scientific journal PNAS. The first author of the paper is Meenakshi Ambati, a senior at Albemarle High School who won several national and international science competition awards for the work. As a volunteer in Gelfand’s laboratory, she initially employed bench laboratory techniques.
When the pandemic all but shut down normal laboratory operations, she was able to continue working on computational analyses, which ultimately gave the overall study its multi-pronged approach.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among those over 50 years of age around the world (Ambati et al. 2003). The dry form of AMD is characterized by degeneration of the retinal pigmented epithelium (RPE), a specialized monolayer of cells lying external to the retinal photoreceptors (Ambati & Fowler, 2012).
Progressive RPE degeneration in the central portion of the retina known as the macula leads to photoreceptor cell death and consequent vision loss over several years (Shen et al., 2020). Dry AMD, which accounts for approximately 90% of the 200 million global cases of AMD (Wong et al., 2014), has no FDA-approved therapy (Mitchell et al., 2018).
In dry AMD, areas of RPE degeneration display abnormal accumulation of Alu RNAs (Kaneko et al., 2011), which are noncoding RNAs transcribed from the highly abundant family of Alu repetitive elements in the human genome (Kazazian & Moran, 2017). These Alu RNAs as well as the related mouse retrotransposon B2 RNAs are cytotoxic (Kaneko et al., 2011; Dridi et al., 2012), as they activate the NLRP3-ASC inflammasome (Tarallo et al., 2012), a multiprotein complex that acts as a cellular danger sensor that responds to a diverse set of inflammatory stimuli (Latz, 2010; Ambati et al. 2013).
In response to various danger signals, the proteins NLRP3 (nucleotide binding domain, leucine-rich repeat receptor, and pyrin domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and pro-caspase-1 assemble into a macromolecular platform known as the ASC speck (Masumoto et al., 1999).
The defining molecular event of inflammasome activation is autocleavage of pro-caspase-1 into active caspase-1. Active caspase-1, in turn, enzymatically cleaves two interleukins (ILs), IL-1β and IL-18, from their inactive pro-form to their mature, active forms. Active IL-1β and IL-18, which are elevated in dry AMD macrophages and RPE cells, respectively, are pro-inflammatory cytokines. In dry AMD, activation of this inflammasome occurs both in RPE cells (Tarallo et al., 2012) and in macrophages (Eandi et al., 2016), and leads to retinal cell death.
Despite dozens of clinical trials over two decades, no treatment has yet proven effective for dry AMD (Mitchell et al., 2018). We sought to identify a novel therapy for dry AMD by employing the concept of drug repurposing (Boguski et al., 2009). Specifically, we hypothesized that an existing drug that is FDA-approved for another disease and that shares structural similarity to a known inflammasome inhibitor might be effective against dry AMD.
Here we demonstrate that fluoxetine, which is FDA-approved for major depressive disorder, contains a structural moiety present in a known NLRP3 inhibitor and that it directly interacts with NLRP3 and inhibits its assembly and activation. Further, fluoxetine inhibits Alu RNA-induced RPE degeneration in mice. We also present evidence from two health insurance databases that fluoxetine use is associated with reduced incident dry AMD, suggesting that it potentially could be repurposed.
reference link :https://www.biorxiv.org/content/10.1101/2021.01.11.425135v1.full
More information: Meenakshi Ambati et al, Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2102975118