Study suggests potential therapy for second most common form of dementia
Written by Bob Shepard
Drugs that boost the function of a specific type of neurotransmitter receptor may provide benefit to patients with the second most common type of dementia, according to research by scientists at the University of Alabama at Birmingham published today in the Journal of Neuroscience.
Frontotemporal dementia, known as FTD, is a devastating disease in which patients have rapid and dramatic changes in behavior, personality and social skills. The age of onset for FTD is relatively young, usually striking patients in their mid- to late 50s. The prognosis is grim; patients quickly deteriorate and usually die within 10 years after onset. Currently, there is no effective treatment for FTD.
The UAB research team’s effort focused on mutations in certain genes, primarily in the Microtubule Associated Protein Tau gene. An accumulation of tau protein is associated with Alzheimer’s disease, the most common form of dementia; but little is known how tau mutations affect specific brain regions and cause FTD.
The UAB researchers used a new mouse model expressing human tau with an FTD-associated mutation. These mice demonstrate physical behaviors similar to those seen in humans with FTD — compulsive, excessively repetitive actions such as grooming, for example. The mice also had impaired synaptic and network function in certain brain network regions.
“We found that mutant tau impairs synapses — the connections between neurons — by reducing the size of the anchoring sites of an essential glutamate receptor called NMDA,” said Erik Roberson, M.D., Ph.D., associate professor in the Department of Neurology and primary investigator for the study. “Reduction of the anchoring sites left fewer NMDA receptors available at the synapse to receive excitatory signals, thus limiting synaptic firing and network activity.”
The team then employed cycloserine, a drug already approved for use by the FDA, which is known to assist NMDA receptor function. This boost of NMDA receptor function was able to restore synaptic firing and thereby restore network activity in the animal model. The restoration of normal network activity reversed the behavioral abnormalities seen in the mice.
“This study provides mechanistic insight into how a tau mutation affects specific brain regions to impair a network,” said Roberson. “It also provides a potential therapeutic target, the NMDA receptor, which appears to correct the network and behavioral abnormalities.”
Roberson’s team hypothesizes that increasing NMDA receptor function may benefit human FTD patients. With further preclinical validation, this hypothesis could be tested in clinical trials using the already available drug cycloserine.
Dr. Marissa Natelson Love Awarded ACA Grant
Dr. Marissa Natelson Love, a UAB Memory Disorders Fellow, was awarded a grant November 14, 2014, from Alzheimer’s of Central Alabama (ACA) at their Annual Meeting to assist in funding research at UAB on Clinical Correlates of Family Quality of Life in Dementia. Dr. Natelson is pictured here accepting the award from Alacare President John Beard, ACA Executive Director Miller Piggott, and ACA Vice President for Research Dr. Lindy Harrell.
Breakthrough treatments find a new way forward
Breakthrough treatments find a new way forward
By Matt Windsor • Photography by Steve Wood • Illustrations by Echo Medical Media
On September 3, 1928, Alexander Fleming came back from vacation and started washing dishes in his lab. Petri dishes, that is. Most people know what happened next: He found a strange, bacteria-killing mold on one plate. It turned out to be penicillin, the first antibiotic, which has gone on to save millions of lives. Nearly 100 years after Fleming’s accidental discovery, we have invented machines to make our own serendipity. But the problems we’re trying to solve are much harder. An antibiotic can kill most bacteria it encounters, but cures for intractable diseases such as Parkinson’s, diabetes, or cancer will have to come from highly specific drugs—or combinations of several drugs.
You’ll still find petri dishes in modern labs, but Fleming wouldn’t recognize much else. Scientists today use genetic sequencing machines to pinpoint the underlying causes of disease. Then they turn these targets over to tireless mechanical arms for high-throughput screening, which sifts through hundreds of thousands of compounds to find the right combination to hit these bullseyes. This high-tech wizardry has led to an information explosion. Every day, it seems, researchers are identifying new ways to stop breast cancer or Alzheimer’s. But what next? There are so many targets, and drug discovery is so expensive, that most promising finds will never make it to patients.
“The government is good at funding basic research to identify drug targets, and Big Pharma is good at putting drugs through clinical trials,” says Andrew West, Ph.D., associate professor of neurology at UAB (pictured above). “But all of the in-between work, the preclinical and drug development components, is called the ‘valley of death’ for research, because nobody funds it; nobody pays attention to it.” The “valley of death” metaphor is all too real for patients. “You get a diagnosis of Parkinson’s disease, and there is nothing you can do to stop it,” West says. “The best advance we have, L-dopa, was developed 50 years ago. There’s really been no breakthrough like that since.”
Machines at Southern Research Institute select the most promising compounds identified by high-throughput screening tests
Bridging the Valley of DeathBut West sees hope on the horizon. For years, he has been studying LRRK2 (pronounced “lark two”). His research shows that this enzyme plays a key role in the cell death that causes Parkinson’s. He believes that LRRK2-blocking drugs could be “the first disease-modifying treatment available for Parkinson’s.” And thanks to a unique partnership between UAB and Birmingham-based Southern Research Institute, he has the chance to prove it.
The Alabama Drug Discovery Alliance (ADDA) is a funding agency and a pharmaceutical company rolled into one. It offers UAB investigators the financing they need to pursue high-potential research. But it also surrounds them with experienced development teams from Southern Research, which has produced seven Food and Drug Administration (FDA)-approved drugs. And it protects and markets their discoveries through UAB’s Institute for Innovation and Entrepreneurship (IIE). West’s lab provided the crucial targeting information for LRRK2. Southern Research’s high-throughput screening robots then identified thousands of potential compounds to block the enzyme. The institute’s medicinal chemists tweaked the most promising to make them more powerful and efficient, and data from the cutting-edge spectroscopy machines at UAB’s Central Alabama High-Field Nuclear Magnetic Resonance Facility helped make these compounds even better. West studies the best candidates in his lab’s sensitive models of Parkinson’s disease. Now, after an investment of several years and millions of dollars, he hopes to have his LRRK2 inhibitor ready for initial human testing in 2015. “Based on our successes,” West says, “we have an excellent opportunity to produce the next revolutionary drug for Parkinson’s disease.”
Risk and RewardPatients worldwide would benefit from that drug. Thanks to the ADDA’s unique financial arrangement, UAB and Southern Research—and by extension, the citizens of Birmingham and Alabama—would see an economic boost as well.
When their scientists find a potential drug target, most universities head to the patent office. Then they try to interest pharmaceutical companies in signing licensing agreements to actually develop that drug. But with the ADDA, “we wanted to develop the pipeline in-house with our own funds,” says Rich Whitley, M.D., ADDA director and Distinguished Professor of Pediatrics at UAB (pictured at right). “Then, when we get something, we’ll go talk to industry. Instead of selling this intellectual property for a million dollars, it’s going to be $10 million plus royalties down the road.”
Partnerships with pharmaceutical companies are still essential to success, Whitley notes. It takes a billion dollars, on average, to bring a drug to market. (Follow the process in “7 Steps to a Brand New Drug” below.) But attracting the interest of Big Pharma is harder than it used to be.
Scientists at major pharmaceutical companies may be working on a hundred different targets, says Mark J. Suto, Ph.D., vice president for drug discovery at Southern Research, who has spent 30 years designing drugs at companies both large and small. “And they have investors and boards of directors telling them what they need to do, so they tend to be conservative. The programs they move ahead are the ones with less risk.” That’s where the ADDA really shines, Suto says. “Our investigators are not worried about earnings per share. We can take risks, look at very novel targets, and ‘de-risk’ them. We can find those molecules and go to our partners and say, ‘This works.’”
A Magic Bullet?As a young investigator at the National Institutes of Health (NIH), Anath Shalev, M.D. (pictured at left), made an interesting basic science discovery. More than a decade later, Shalev is the director of UAB’s Comprehensive Diabetes Center. And her discovery could spark a revolution in diabetes treatment.
High blood sugar is the hallmark of diabetes. Shalev, who was studying the insulin-producing beta cells in the pancreas, found that one particular gene goes into overdrive when blood sugar rises: the one that makes thioredoxin-interacting protein, or TXNIP (pronounced “ticks-nip”). Her research was focused elsewhere, but Shalev kept wondering what all that TXNIP was doing to the body. “I just had to know,” she says. Over several years, she doggedly followed TXNIP until she had the answer: It’s the trigger that makes beta cells commit suicide, robbing the body of the insulin it needs to survive.
Shalev initially faced skepticism. “People said, if TXNIP is so important, why didn’t anyone find it before?” she recalls. But she kept at it; when she deleted the TXNIP gene in diabetes-prone animals, they didn’t get the disease. Blocking TXNIP in mice with diabetes saved beta cells and actually boosted insulin production. She found the same effects in human islets. Bringing TXNIP down to normal levels also reduced diabetes complications in the heart, kidneys, and eyes.
Then there was another strong indication: Shalev discovered that the blood pressure drug verapamil, which also happens to lower TXNIP production, protects mice against diabetes. A drug specifically designed to stop TXNIP “could be a powerful treatment for both type 1 and type 2 diabetes,” she says. “In general I don’t believe in magic bullets, but this seems to be one.”
Faced with Shalev’s mountain of evidence, other diabetes researchers are now racing into TXNIP studies. Big Pharma is sniffing around, too, even though the failure of a high-profile class of medications known as TZDs—unrelated to TXNIP—has left companies skittish of diabetes drugs. “Because we have it this far, they’re willing to listen,” Shalev says. “They say, once you have more, tell us.”
Without the ADDA, the search for a TXNIP drug could have remained in this limbo indefinitely, Shalev says. Instead, she has already worked with Suto and his Southern Research team to identify a potential drug—known in the industry as a “lead compound.” It is very effective, much more so than verapamil. Now the scientists are deep into the arduous testing required to prove that their drug has no significant side effects; preliminary results show it does not.
Shalev is sanguine enough to know that drug discovery is a difficult business. “There always is a risk of failure, but in this case also potentially a very high yield,” she says. “It could have a dramatic impact, and as someone who treats patients with diabetes, that’s very exciting.”
Nothing Ventured, Nothing GainedEvery potential ADDA project is vetted to make sure it addresses an unmet medical need. Meanwhile, the intellectual property experts at UAB’s IIE do extensive studies to ensure “there is a market for the product,” says IIE director Kathy Nugent, Ph.D. “It’s not enough to be scientifically interesting; it has to have commercialization potential before we decide to invest in it.”
Projects passing these initial tests receive a two-year financial commitment from UAB and Southern Research. “After someone gets funded, I build a team around the project,” says Maaike Everts, Ph.D., ADDA associate director and associate professor in the UAB School of Medicine. The teams meet regularly to share data and quickly adapt to any obstacles they encounter. Despite all the technology involved, “drug discovery comes down to human interaction,” Everts notes. “It’s about people sitting in a room and hashing it out.”
The end goal is always in view, Suto adds. “We set up timelines and milestones,” he says. “And we are willing to stop projects” if they just aren’t panning out. “We had a group from [pharmaceutical giant] Pfizer here, and they thought that was unique; they said they don’t see that very much in academic research.”
Inside OutSometimes, a project just needs a fresh set of eyes. Joanne Murphy-Ullrich, Ph.D. (pictured at right), a professor in the Division of Molecular and Cellular Pathology, has spent her career studying thrombospondin-1 (TSP-1), a protein living in the gaps between cells known as the extracellular matrix.
TSP-1 is an enabler. Murphy-Ullrich’s lab discovered that one of its main jobs is to switch on transforming growth factor (TGF) beta. An important part of the wound-healing process, TGF-beta is also linked to cancer metastasis, diabetic complications, and autoimmune diseases. “TGF-beta is an attractive therapeutic target for many diseases, but altering it directly can have side effects,” Murphy-Ullrich says. “More specific means of controlling TGF-beta action are needed. Blocking TSP-1 is one approach.”
A graduate student in Murphy-Ullrich’s lab found the specific peptide sequence in TSP-1 that activates TGF-beta, and a postdoctoral student found a competing sequence that could stop that activation. Though the peptide was active in animal models of diabetes-induced fibrosis, its half-life was too short be a drug; what wasn’t clear was how to make that happen. “I had this great observation and molecular mechanism, but I didn’t know how to improve the peptide’s druglike characteristics,” says Murphy-Ullrich. “It was the ADDA that turned this around.”
Suto quickly noticed that Murphy-Ullrich was already most of the way there with her peptide sequence. His team of medicinal chemists has improved the peptide’s stability, and Murphy-Ullrich’s lab has shown that the druglike peptide reduces multiple myeloma tumor burden and bone loss in animal models. New NIH funding has spurred further drug development.
Scientific AttractorsUAB’s investment in drug discovery is proving to be a powerful recruitment tool as well. “The ADDA played a large part in my decision to move to Alabama in 2007,” West says. Fran Lund, Ph.D. (pictured above), who joined UAB as Department of Microbiology chair in 2012, says, “the opportunity to even apply for an ADDA grant was a big factor in my decision to come to Birmingham.”
For decades, Lund has been studying the enzyme CD38, which is overproduced in several types of cancers—particularly leukemia and multiple myeloma—often seen in older patients. These patients can have strong adverse reactions to chemotherapy—so strong they can’t continue treatment. But Lund’s data indicates that a drug to block CD38, added to standard chemotherapy, could dampen these side effects, allowing patients to continue potentially life-saving treatment.
Lund has shown that this works in genetically modified animal models, but “we’re at a point in our research where a drug company is not going to pick it up and pay for it,” she says. “And the NIH doesn’t necessarily pay for these kinds of projects.” ADDA support offers “a great opportunity to look for inhibitors,” she says. “If that looks interesting, then we can go for funding with pharmaceutical companies or the NIH.”
"After someone gets funded, I build a team around the project. Drug discovery comes down to human interaction." —Maaike Everts
Immediate ImpactThe ADDA has already led to major funding success. This spring, a $35-million grant from the National Institute of Allergy and Infectious Diseases established the UAB-led Antiviral Drug Discovery and Development Center. The center brings together top virologists from around the country to create drugs for high-profile viral threats such as influenza, SARS, dengue, and chikungunya.
“These viruses are of the highest priority for the U.S. government,” says Whitley. The consortium includes a UAB-Southern Research team led by Whitley that will work on new flu therapies. Scientists at Southern Research will develop and perform the high-throughput screening tests for all of the center’s teams nationwide. “And it never would have happened if the NIH hadn’t seen the success of the ADDA,” Whitley says.
The ADDA model has also paved the way for another UAB-Southern Research partnership to develop and market medical devices. The collaboration will be led by a prominent expert in the field with dual appointments in the UAB Department of Biomedical Engineering and at Southern Research.
Major InvestmentUAB President Ray L. Watts, M.D., has made it clear that drug discovery efforts are a major focus of the $1-billion Campaign for UAB. “Through the ADDA, we have approximately 18 new disease-changing therapies in the pipeline, and we’re pushing hard to bring them as new treatments as rapidly as possible,” Watts says.
Getting through the first phase of human testing can take several million dollars, so significant investment from community partners is necessary, Watts points out. Many benefactors have already shown support for these projects. Andrew West’s work on LRRK2 inhibitors “has been accelerated significantly through local philanthropic support,” he says. “Many people in this area are disappointed to see that the government doesn’t fund a lot of research into Parkinson’s disease cures.”
Jump-starting worthy projects thrills everyone involved in the ADDA. “It’s always the last sentence in a new research study: ‘This is a great opportunity to cure cancer,’ or whatever the disease may be,” says Everts. “With the ADDA we’re saying, ‘Let’s take the next step and really do it.’”
Hit Parade: Current projects in the ADDA pipeline include • LRRK2 (Parkinson’s) • Tau-Fyn (Alzheimer’s) • 14-3-3theta (Parkinson’s) • RPS25 (cancer) • SUMO (myc-driven tumors) • RANK (bone metastases) • RNA polymerase I (cancer drug screening) • CD38 (multiple myeloma and other B cell-derived cancers) • Cytochrome C oxidase (chemotherapy resistance) • TDP1 (cancer) • HuR (glioma) • TSP1 (multiple myeloma) • DNA methyl transferase (cancer) • Mtb siderophores (tuberculosis) • HO-1 (kidney disease) • TXNIP (diabetes) • ATM-NSB1 (sensitization of cancer to radiotherapy) • PTC (Hurler syndrome)
7 Steps to a Brand New DrugIt takes 10 to 15 years and more than $1 billion to develop a new drug. Here’s how it works:
Step 1: Find a target Before you can design a drug, you need a target: a specific enzyme to block, or a signaling molecule to silence. Years of research pointed Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center, to TXNIP, a protein that kills insulin-producing beta cells.
Step 2: Make an assay Once you have a target, you must find something that can affect it—and a way to tell it has been affected. That means designing a reliable and reproducible chemical test, or assay. Such a test might involve a fluorescent biomarker that lights up if a compound blocks your enzyme. Finding the right assay can take several years.
Step 3: Screen for hits With an assay in place, you look for active compounds—molecules that interact with your target very specifically. Southern Research’s high-throughput screening facility tests anywhere from 50,000 to 300,000 different compounds, looking for “hits.”
Step 4: Take your lead The best match becomes your lead compound, but it won’t be perfect. It may not stay in the body long enough, or it could produce unacceptable side effects. Medicinal chemists tweak the lead compound to increase its potency and remove unwanted interactions elsewhere in the body. Meanwhile, additional screening runs find secondary compounds as backups in case the first compound doesn’t pan out.
Step 5: Preclinical development The lead compound goes into animal models of your disease. At this stage, researchers measure efficacy, determining the compound’s selectivity for its target, and look for its mechanism of action. (The more you know about how it works, the easier it is to make it work better.) Success means you can make an investigational new drug (IND) application to the Food and Drug Administration (FDA) to begin human testing.
Step 6: Clinical development Human testing begins with a phase 1 trial, with anywhere from a handful to 100 subjects. The main goal is to find out if your drug is safe. Then, in a phase 2 trial with 100 to 200 patients, you can ask how well it works, and which doses are best. In phase 3 trials, generally involving thousands of patients, you find out how well it works compared with standard treatments for your disease. The trials process can take six years or more.
Step 7: FDA approval After successful phase 3 trials, you can finally file an NDA—New Drug Application—with the FDA to bring your drug to market. Approval can take one to two years. There’s no time to lose; your patent expires 20 years from the date you filed your NDA.
Image MagnetMost high-end lab equipment is inaccessible to the public eye, but one of UAB’s most powerful drug-discovery tools is clearly visible from the Campus Green.
The Central Alabama High-Field Nuclear Magnetic Resonance (NMR) Facility, which opened last year in a gleaming new space on the Chemistry Building’s ground floor, gives researchers invaluable insight into the inner workings of test compounds and their protein targets.
The facility’s four NMR machines use powerful magnets to excite hydrogen atoms. Recording the signatures produced by those atoms gives researchers precise structural information about a sample. The centerpiece is an 850 MHz Bruker BioSpin machine, one of the South’s largest. It gives researchers crucial structural data about even the largest proteins, letting them home in on “binding pockets” where they could dock new drugs.
Southern Research scientists have worked closely with the facility to evaluate lab-created LRRK2 inhibitors against Parkinson’s disease, says NMR director N. Rama Krishna, Ph.D., UAB professor of biochemistry and molecular genetics. The facility also is evaluating drug candidates for UAB researchers working on cancer, heart disease, infectious diseases, and more. And as word of its capabilities has spread, researchers across the Southeast are starting to send in samples for analysis. (In the image above, UAB's Krishna and Southern Research Institute researchers have collaborated in developing a novel high-field NMR-based protocol for determining how compounds bind to target proteins—in this example, the inhibitor monastrol and kinesin-5 protein Eg5, a cancer target.)
“The range of applications is amazing,” Krishna says. “NMR is one of the most versatile tools for drug discovery research. This facility puts UAB at the forefront of the field.”
Learn how it works on The Mix, UAB’s research blog.
Biotech: The Next GenerationStudents in the biotechnology master’s degree program in the School of Health Professions don’t just have a front row seat to UAB’s drug discovery efforts—they’re a part of the action. Students are assigned to dig into UAB’s intellectual-property portfolio to find new commercialization opportunities, explains Kathy Nugent, Ph.D., director of the program and UAB’s Institute for Innovation and Entrepreneurship.
“It gives students valuable experience, and they work closely with investigators,” Nugent says. These hands-on projects are just one part of a unique program, she adds. “We’re taking everything students learned in their undergraduate careers and showing them how to apply it.” That includes understanding business models in life sciences and assessing the steps necessary to commercialize a product. To succeed in today’s competitive biotech marketplace, Nugent says, “you have to speak both languages: science and business.”
• Give something and change everything to help accelerate drug discovery at UAB.
Investing in Breakthroughs
The Jurenko name is indelibly linked with the UAB Department of Neurology, so consistent has been the Huntsville couple’s support of the department’s goals. Since 2007, John Jurenko, the retired vice president of sales and marketing at ADTRAN, a company he co-founded in 1985, and his wife, Ruth, have made gifts to advance numerous initiatives within the department. Among these are the John A. and Ruth R. Jurenko Neurological Research Laboratory, the John A. and Ruth R. Jurenko Research Scholar Fund, and the UAB-HudsonAlpha Collaborative Project in the Genetics and Genomics of Parkinson’s Disease.
Their latest gift, to establish the John A. and Ruth R. Jurenko Endowed Professorship in Neurology, enabled department chair David G. Standaert, M.D., Ph.D., to recruit one of the country’s leading Parkinson’s disease researchers. In 2007, Andrew B. West, Ph.D., was recruited from Johns Hopkins University to UAB, where he was named the John A. and Ruth R. Jurenko Research Scholar and became director of the John A. and Ruth R. Jurenko Neurological Research Laboratory in the UAB Center for Neurodegeneration and Experimental Therapeutics (CNET). In February 2013, he became the inaugural holder of the John A. and Ruth R. Jurenko Endowed Professorship in Neurology.
John Jurenko first encountered the Department of Neurology as a Parkinson’s patient, but was quickly impressed by the innovative research taking place. “My original contact with the department was because of the disease, but then I got to know the people there. They are exceptional people, both professionally and personally,” he says. “In discussion with them, I learned that they wanted to grow the department, and I figured I could help. They mentioned Andy West and his talent and that they’d like to have him. So I said, ‘Well, let’s go get him.’”
According to Standaert, philanthropic support like the Jurenkos’ has been key to making the UAB Department of Neurology and its associated divisions and centers the hives of innovation they are today. “Almost all of the major faculty recruitments we have done have been based on philanthropic gifts,” he says. “Their willingness to support our vision has enabled the tremendous growth we have experienced in less than a decade. When I first came to UAB in 2006 to lead CNET, it was just me. Now the center comprises more than 50 scientists, students, postdocs, and staff.” This philanthropic investment in research has contributed to an explosion in Parkinson’s discoveries, Standaert says. “The amount we’ve learned in the past five years exceeds everything we knew from the previous 200 years. We are deeply grateful to John and Ruth Jurenko for helping us achieve so much in such a relatively short period of time.”
According to West, “Meaningful advances in neurodegeneration research are very hard won. The John A. and Ruth R. Jurenko Professorship in Neurology allows us to accelerate the process and provides key resources to address critical questions that can’t wait for traditional funding mechanisms. With the support of the Jurenkos, we can focus on addressing critical bottlenecks and hasten the identification of novel neuroprotective therapeutics.”