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 BreakthroughsRuth and John Jurenko establish endowed professorship in Neurology.
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.”
New device to control seizures proving its worthIt has been 30 days since neurologists at the University of Alabama at Birmingham turned on the neurostimulator implanted in Sarah Conner’s brain to control her seizures.
In that short time, she can already say, “I’m doing pretty good."
Conner, 24, has suffered from seizures for 10 years. In June, she became the first patient in the Southeast to receive a new device called a responsive neurostimulator since its approval by the Federal Drug Administration last year.
UAB neurosurgeon Kristen Riley, M.D., implanted the RNS system, developed by NeuroPace, into Conner’s brain. It includes an electrical generator, about the size of a flash drive, which is implanted in the skull. Electrodes are run to the locations in the brain known to cause seizures.
“It is designed to record a patient’s specific brain activity and recognize patterns that are associated with seizures,” said Riley, associate professor in the Department of Neurosurgery. “The RNS system then delivers stimulation in order to help modulate and control the seizures.”
Prior to receiving the RNS system, Conner experienced multiple semi-partial seizures every day, lasting anywhere from 10 seconds to more than a minute. When they hit, she lost all ability to function.
“It affected my motor function and sensory perception,” Conner said. “I couldn’t tell where my hand was, for instance. I couldn’t even do simple functions such as open a door because my body wouldn’t respond. It was as if I’d forgotten how to do it.”
A month after the surgery, UAB neurologist Neil Billeaud, M.D., turned on the device. At a follow-up visit 30 days later, Conner reported dramatic improvement.
|“This is not a treatment that will cure epilepsy. This is a treatment that will help control seizures in a very specific group of patients who otherwise are not candidates for surgery. I don’t expect too many patients to become seizure-free; but if we can decrease their seizures by even half, we can make huge improvements in their lives.”|
The RNS system is constantly recording Conner’s brain activity, and the data is downloaded to a laptop computer. If Conner says she had a flash last week, Billeaud can pinpoint the specific time and see what brain activity was occurring. As the system learns more about specific patterns that indicate a seizure is likely, Billeaud can tweak the parameters to make the RNS system even more effective in controlling seizures.
Jerzy Szaflarski, M.D., Ph.D., professor in the Department of Neurology and director of the UAB Epilepsy Center, says data from research studies dating back several years indicate that many patients will respond to the stimulation and have significant reduction in their seizures.
“This is not a treatment that will cure epilepsy,” he said. “This is a treatment that will help control seizures in a very specific group of patients who otherwise are not candidates for surgery. I don’t expect too many patients to become seizure-free; but if we can decrease their seizures by even half, we can make huge improvements in their lives.”
Conner agrees. She is working on a degree in elementary education and had episodes in the past in which she had a seizure while student-teaching. The reduction in seizures will give her more independence.
“I’ll be able to do more,” Conner said. “For instance, I’ll be able to drive. I’m 24, and I’ve never driven a car. The big hindrance with the seizures was that, when they hit, I couldn’t function and was unable to do anything. Now I simply feel this flash, and then it goes away without affecting my motor function.”
The RNS system is for patients who have severe seizures but do not respond to medications and are not candidates for surgery because the location of their seizure onset is at a sensitive part of the brain. It is also only for patients whose seizure onset can be traced to just one or two locations in the brain.
“We’re very excited to offer this therapy to our patients who are not candidates for more traditional therapies for epilepsy,” Szaflarski said. “We see multiple patients like that every year, and the RNS system could make a huge difference in the lives of those patients. There is already data to show that the quality of life of those patients has improved significantly with RNS.”
For more information on the RNS system, contact the UAB Epilepsy Center or make an appointment via the Kirklin Clinic at 205-801-8986.
Compliments of Bob Shephard
Changes in the eye might predict onset of frontotemporal dementiaChanges to the eyes might help diagnose the onset of frontotemporal dementia, the second most common form of dementia, according to new research from scientists at the University of Alabama at Birmingham, Gladstone Institutes and the University of California, San Francisco.Findings published today in the Journal of Experimental Medicine show that a loss of cells in the retina is one of the earliest signs of frontotemporal dementia in people with a genetic risk for the disorder — even before any changes appear in their behavior.
The researchers studied a group of individuals who had a certain genetic mutation that is known to result in FTD. They discovered that, before any cognitive signs of dementia were present, these individuals showed a significant thinning of the retina compared with people who did not have the gene mutation.
“This finding suggests that the retina acts as a type of window to the brain,” said Erik Roberson, M.D., Ph.D., associate professor in the Department of Neurology at UAB and a study co-author.
Roberson and Timothy Kraft, Ph.D., associate professor in the UAB Department of Vision Sciences, collaborated with the lead investigators, Li Gan, Ph.D., from Gladstone and Ari Green, M.D., associate professor of neurology at UCSF.
“Retinal degeneration was detectable in mutation carriers prior to the onset of cognitive symptoms, establishing retinal thinning as one of the earliest observable signs of familial FTD,” Gan said. “This means that retinal thinning could be an easily measured outcome for clinical trials.”
Although it is located in the eye, the retina is made up of neurons with direct connections to the brain. This means that studying the retina is one of the easiest and most accessible ways to examine and track changes in neurons.
This electroretinogram image shows photoreceptor activity from two mice. The gray line represents the animal model that has frontotemporal dementia, the black line is the control or healthy mouse. The large negative spike in the diagram indicates a reduction of ganglion cells in the retina of the mouse model that mirrors human dementia.Roberson’s laboratory has been studying an animal model for FTD. Using a process called ERG, or electroretinogram — similar to an EKG — Roberson and Kraft showed that the retinas in mice with FTD had a loss of ganglion cell function; these cells are responsible for transmitting signals from eye to brain. That data, along with additional ERG studies that Kraft performed in California, aligned well with comparable human studies conducted by Gladstone and UCSF.
“We have a more complete understanding about how the retina functions as opposed to the operations of the complex brain,” said Kraft. “That makes it much easier to use the retina as a tool for better understanding FTD.”
The researchers also discovered new mechanisms by which cell death occurs in FTD. As with most complex neurological disorders, there are several changes in the brain that contribute to the development of FTD. In the inherited form researched in the current study, this includes a deficiency of the protein progranulin, which is tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm.
However, the relationship between neurodegeneration, progranulin and TDP-43 was previously unclear. Using the UAB mouse model of FTD, the scientists were able to investigate this connection for the first time in neurons from the retina. They identified a depletion of TDP-43 from the cell nuclei before any signs of neurodegeneration occurred, signifying that this loss may be a direct cause of the cell death associated with FTD.
TDP-43 levels were shown to be regulated by a third cellular protein called Ran. By increasing expression of Ran, the researchers were able to elevate TDP-43 levels in the nucleus of progranulin-deficient neurons and prevent their death.
“The results of this study have shown that we can use the thinning of retinal cells as a marker for this type of dementia,” said Roberson. “Further studies may also help determine whether the changes in the retina can be utilized as a marker of disease progression. We may also be able to use the retina as a means of gauging the effectiveness of new therapies.”
Researchers from the University of Texas Southwestern also collaborated on this study. It was funded by the Consortium for Frontotemporal Dementia Research, Bluefield Project to Cure FTD, National Institutes of Health, UCSF Resource Allocation Program, UCSF Alzheimer’s Disease Research Center, Chartrand Foundation and Clinical & Science Translational Institute, Howard Hughes Medical Institute, Alzheimer’s Association, Welch Foundation, and Alzheimer’s Drug Discovery Foundation
By: Bob Shephard