UA researchers identify possible cause of statin side effects in cholesterol patients

TUSCON, Ariz.—While probing genetic mutations as a drugdiscovery platform for developmental brain disorders, researchers at theUniversity of Arizona (UA) stumbled upon an unexpected discovery that couldexplain why some patients being treated for high cholesterol may experiencenegative cognitive side effects while taking statins, a class of globaltop-selling cholesterol-lowering drugs.

Publishing their findings in the peer-reviewed journal Disease Models & Mechanisms, theresearchers believe they have stumbled upon important insights into why somepatients experience fuzzy thinking and memory loss while taking statins.

"This project started as a tangent off something completelydifferent, and was a serendipitous discovery," says neuroscientist Dr. Linda L.Restifo, a principal investigator on the project and a professor ofneuroscience, neurology and cellular and molecular medicine at UA. "We were screeninga library of compounds with a drug repurposing strategy, with the hope ofrepurposing a drug about which a fair amount was known and had low toxicity,and to get approval for a new indication instead of taking the approach ofusing a combinatorial library or random compounds. Our hope was to get anactual marketable drug in the clinic sooner."

The actin-bundling protein fascin is a key mediator of tumorinvasion and metastasis and its activity drives filopodia formation, cell-shapechanges and cell migration. Small-molecule inhibitors of fascin block tumormetastasis in animal models. Conversely, fascin deficiency might underlie thepathogenesis of some developmental brain disorders.

To identify fascin-pathway modulators, the UA team devised acell-based assay for fascin function and used it in a bidirectional drugscreen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arborsmanifest the "filigree" phenotype. Taking a repurposing approach, we screened alibrary of 1040 known compounds, many of them U.S. Food and Drug Administration-approved drugs, for filagree modifiers.

Based on scaffold distribution, molecular-fingerprintsimilarities and chemical-space distribution, the library had high structuraldiversity, supporting its utility as a screening tool. The UA team identified34 fascin-pathway blockers (with potential anti-metastasis activity) and 48fascin-pathway enhancers (with potential cognitive-enhancer activity). Thestructural diversity of the active compounds suggested multiple moleculartargets. Comparisons of active and inactive compounds provided preliminarystructure-activity relationship information.

While engaged in that research, Restifo and her colleaguesnoted that brain cells being treated with statin drugs had unusual swellingswith neurons, which the neuroscientist describes as "beads on a string." Thus,they observed that statin-induced neurotoxicity is enhanced by fascindeficiency.

"My working hypotheses in all of this is that there is asmall number of patients who are genetically susceptible to statinneurotoxicity," says Restifo. "Because of the way we did the drug screens withneurons, which we compared to normal neurons, we actually did a geneticdemonstration of this sensitivity in the lab. Our hope is that we can use ourlab's system to find the genes that make certain individuals very sensitive tostatins."

Although the researchers do not yet know why the beads form,they believe that further investigation of them will inform why some peopleexperience cognitive declines while taking statins. For now, with multipleexternal grants pending, Restifo and her colleagues hope their research willbetter inform the medical community and patients.

"If we are able to do genetic studies, the goal will be tocome up with a predictive test so that a patient with high cholesterol could betested first to determine whether they have a sensitivity to statins," Restifosays. "The older I get and the more medication I have to take myself, I thinkabout the 'first do no harm' part of medicine. We have heard a lot aboutpersonalized medicine, but the first place to use it is to prevent side effectsin small groups of people who have specific genetic susceptibility to theseside effects."

But the research may have other implications beyondcholesterol treatment. The findings also address two major clinical problemsthat do not initially seem related: invasive cancers, including most braintumors, cause death due to invasion or migration, which are not inhibited bycurrently available cancer treatments; and developmental brain disorders arenot treatable with drugs that enhance cognitive function.

"For both of these unmet medical needs, a major obstacle hasbeen the lack of cellular bioassays for compound screening. The actin-bundlingprotein fascin links these two challenging clinical conditions: excess fascinpromotes tumor invasion and metastasis, whereas insufficient fascin disruptsbrain development. Thus, the fascin pathway represents a highly desirable drugtarget," the researchers concluded.

Ultimately, Restifo hopes to work with a commercial partnerto bring these discoveries to the clinic.

"I have spoken with a number of companies, and we think wecould use this assay to screen next-generation cholesterol-lowering drugs. Wewould be very interested in collaborating with the pharmaceutical sector. But Ithink if the drug companies are going to jump on the personalized medicinebandwagon, they are going to have to think differently about blockbuster drugsand treat individual patients, instead of putting drugs in the drinking water.I think a more nuanced approach to therapeutics is needed," she says.

The research was funded by awards from the U.S. NationalInstitutes of Health, UA's Center for Insect Science, the state of Florida andthe Menopause & Women's Health Research Center.