Research Feature

Drugs Leading Double Lives

by Tamar Nordenberg


Put tissue paper in the cage of run-of-the-mill mice, and they naturally put their minds to building a nest. But Alzheimer’s disease robs this inclination from the animals, and mice engineered to mimic early-stage Alzheimer’s disease show no such nesting inclinations when they encounter tissue paper.

Yet just 72 hours after these mice received a drug treatment, they began exhibiting the behaviors of their healthy counterparts by making nests. In the same three-day span, their brain levels of amyloid plaques had been reduced by half. What was the agent that caused such a speedy reversal of mental decline and disease pathology? Bexarotene, a drug already approved by the FDA for skin cancer. That preapproval could shave years off the timeline for studying the drug in Alzheimer’s disease. “Drugs that have already been through the arduous FDA approval process, such as bexarotene, have the potential to get to patients much faster,” says new PhD Paige Cramer, who collaborated on the mouse study with lead researcher Gary Landreth, PhD, the Riuko and Archie G. Co Professor of Neuroscience at the School of Medicine. Because of the pre-existing treasure trove of information about their pharmacology, including toxicity and dosing, such already-approved drugs have a huge head start, explains Cramer, who served as first author on the study, published earlier this year in Science.

For more than 5 million Americans with Alzheimer’s disease—and those with other serious conditions with no cure—the 14-year average wait time while a novel drug is developed is untenable. This typical interval between a basic-science discovery and a therapeutic approval, and the 99-percent failure rate for would-be therapies, was summed up by NIH director Francis Collins, MD, PhD, at a recent address to the City Club of Cleveland: “That is not acceptable.”

School of Medicine researchers are among those in academia answering urgent pleas from the NIH and other public health experts—and more importantly, patients and their loved ones—to find speedier paths through the drug development gauntlet. One approach is to take drugs that have already won FDA approval by demonstrating safety and effectiveness in one disease and “repurposing” or “repositioning” them to treat another condition.

“The majority of new chemicals—some nine of every 10—fail in toxicology studies,” points out Krzysztof Palczewski, PhD, the John H. Hord Professor and chair of the Department of Pharmacology. With a $10.1-million NIH grant1, Palczewski is screening drugs approved for various conditions to see if they have the potential to preserve sight in those with retinal diseases. “With an approved drug, we can have 10 to 20 years or more of safety information to help ensure we’re not curing one condition but causing another.”

Repurposing offers a valuable complement to—though it will never eclipse—medical school researchers’ primary focus on developing innovative compounds, says the university’s vice president for research and Allen C. Holmes Professor of Neurological Diseases, Robert Miller, PhD. “It’s wonderful and important to develop your own novel compound, beginning with building a hugely detailed understanding of its biology,” says the neurosciences professor, who also heads up the medical school’s Center for Translational Neuroscience. But that can easily occupy 20 years, he says, so medical school researchers are on the lookout, too, for approved drugs that make sense to study in additional diseases. “What’s really exciting is the immediacy,” Miller says of the repurposing potential exemplified by the Landreth-Cramer and Palczewski studies. “Repurposing can offer a more direct and rapid path from bench to clinic.”

Eye on Approved Drugs

Suffer from depression? Bupropion—brand name Wellbutrin—is approved for that. Want to squelch the smoking habit? Bupropion found a second life, under the name Zyban, with its subsequent FDA nod for this indication. The idea of repurposing a drug isn’t new: In another famous example, the erectile dysfunction drug Viagra (generically called sildenafil) was ultimately approved for the condition in 2005 after a serendipitous side effect clued in researchers looking to broaden the heart’s blood vessels.

But while these additional indications were found largely thanks to happenstance, today’s researchers are relying more on systematic analysis—not fluke findings—to identify approved drugs with untapped potential or even team up previously unrelated medications to treat new conditions. Elaborate computer programs are being developed to match approved drugs with diseases they might work against, such as conditions whose genetic underpinnings make them likely targets. By and large, though, researchers must still rely on their own powers of scientific rationale and methodical testing.

Systematically homing in on approved drugs that could find a new purpose preventing blindness is the current mission for the School of Medicine’s Palczewski. With the grant from the National Eye Institute (NEI), principal investigator Palczewski and a group of Case Western Reserve and additional experts are searching for cures for retinal diseases. In particular, the conditions include age-related macular degeneration (AMD), which is the main cause of blindness in those over age 55; a childhood form of the vision-pillaging condition called Stargardt’s disease; and a condition called retinitis pigmentosa that spirits away a person’s peripheral vision.

It’s crucial that effective treatments be found for these common and serious conditions, explains Marcin Golczak, PhD, an instructor in the school’s Department of Pharmacology and collaborator on the retinal diseases research. “Vision is the main intellectual sense of perception in humans. Its impairment affects our life to a greater degree than loss of any other sense, including hearing, smell, taste or touch.”

The five-year grant was awarded so that School of Medicine researchers from the departments of Pharmacology, Ophthalmology and Visual Sciences, and Biomedical Engineering could continue their ongoing work in the area of retinal diseases. Palczewski’s laboratory has identified vitamin A-related processes that can cause a toxic byproduct to build up in the eye’s retina and degrade vision. Building on this knowledge, Palczewski’s team identified 24 FDA-approved drugs—from antibiotics to treatments for cancer and infectious diseases—that, by the way they work, might thwart this destructive chain of events. And in findings in mice that led up to the NEI grant, 16 of the 24 drugs did, indeed, show benefit in preventing retinal degeneration.

Palczewski’s research team includes co-PI Akiko Maeda, MD, PhD, an assistant professor in the medical school’s departments of Pharmacology and Ophthalmology, who relocated from Japan to work on the project. The group also includes Golczak and additional interdisciplinary experts working within a consortium known as the Retinal Therapeutics Study Group.

Relying on state-of-the-art imaging technologies, including a non-invasive approach developed in Palczewski’s own lab, the research group is screening FDA-approved drugs in animal models of disease to pinpoint those most likely to work in people. Characteristics of interest include their chemical properties, toxicity, targets and side effects. Says researcher Maeda, “If there are FDA-approved drugs that can be used for new treatment applications, we can provide safer options in a shorter development time. And I’m excited that lessons learned from approved drugs will help us develop new medications for these diseases.”

The research team is gearing up for clinical trials in those with age-related macular degeneration, and Golczak says he and his colleagues are “extremely optimistic” that their line of research will lead to breakthrough treatments. “We realize there is still a long way to go before our concepts are introduced into ophthalmology clinics. But we strongly believe that our effort will lead to cures for these currently incurable retinal diseases.” By Palczewski’s estimate, it could take about five years for new cures coming from this research to reach the clinic.

Finding Out Faster: Will It Work?

As for the study of bexarotene, approved as Targretin more than a decade ago for cutaneous T-cell lymphoma, Cramer zeroed in on this drug by puzzling together clues about its potential to break down amyloid-beta plaques—built-up protein fragments long suspected as primary culprits in Alzheimer’s disease. Foundational evidence came from a 2008 discovery in Landreth’s Alzheimer’s lab: The main cholesterol carrier in the brain, Apolipoprotein E (ApoE), participates in clearing the pernicious amyloid-beta proteins from the brain. Based on the knowledge that bexarotene stimulates the retinoid X receptors (RXR) that control how much ApoE is produced, Landreth and Cramer reasoned that by upping ApoE expression in the brain, bexarotene might reverse the cognitive and memory effects in the brain disease—in mice and hopefully, in turn, in people.

And reverse the wreckage it did, says Landreth, the study’s senior author: Not only did the miscreant plaques significantly clear from the mice’s brains within just 72 hours—eventually reducing by 75 percent by 14 days—but the animals rapidly showed signs of improved learning and memory and returned to healthy behaviors, including nesting.

Along with this turnaround in symptoms that “stunned” even Landreth himself is the striking fact that the preclinical research came with a low price tag of about $250,000—an amount contributed by the Blanchette Hooker Rockefeller Foundation and NIH2. By Landreth’s description, the study “was run on fumes, by a single talented graduate student and with very modest financial support.”

In the Alzheimer’s research and care community, hopes are high that bexarotene will work in people, given the dazzling improvements seen in mice. And the medical school scientists are themselves upbeat about its chances of proving effective. Landreth hopes and expects that the drug will be effective in people in an early stage of the disease.

On a cautionary note, Landreth adds, “Let’s be very clear: We have data in mice. Science has fixed Alzheimer’s in mice lots of times, and the translation to humans has failed at the 100 percent level.” But bexarotene is appreciably superior in a sense to some past experimental Alzheimer’s therapies: The biological pathway activated in the bexarotene-tested mice is a naturally occurring process in humans, as well. “The drug is simply enhancing Mother Nature’s process to clear amyloid from the brain,” Cramer points out, “not making essential changes to the way the body works like some compounds tested in the past.”

William H. Thies, PhD, the Alzheimer’s Association’s chief medical and scientific officer, calls the research promising—so promising, he notes, that the association bestowed on Landreth its prestigious Zenith Award to continue his bexarotene research. Landreth and Cramer will test the compound’s impact in healthy people next, and Cramer says that several years of testing in people should crystallize the drug’s potential in Alzheimer’s. The drug’s patent protection recently expired, nullifying one major incentive for pharmaceutical company investment, but Landreth and Cramer are confident that foundation support will see the research through the next phase, and they have formed a company to maintain the research’s momentum.

While awaiting results of the next phases of study, it’s far too early to recommend bexarotene’s use in Alzheimer’s disease, the researchers emphasize. Drugs that have not been sufficiently studied in people with a particular disease might not work, Landreth says, but what’s worse, could have dangerous consequences.

Even if bexarotene fails in continuing research to live up to its bright prospects, the letdown, though major, will have a considerable silver lining for those fighting on for an Alzheimer’s cure. “The already-approved drug’s accelerated road to clinical trials means we’ll know whether this works or not in people really quickly,” says Miller. “This means that if it fails, it will fail quickly, and research energies can be immediately diverted to finding out what will work.” If bexarotene rises to the level of researcher hopes, on the other hand, the drug would represent a quantum leap in treating a disease that until now has been heartbreaking in its indomitability.

1 Research Funded by NIH grant No. 5P30-EY011373-15 2 Research Funded by NIH grant No. 5P50-AG008012-16