Creating a roadmap to bring innovative medical technologies to market

Robert Hergenrother, Ph.D., isn’t a surgeon, but he has done some of his best work in the operating room. In his three decades in the medical device industry, Hergenrother has led engineering teams that have created 15 products, including new technologies for use in brain surgery, wound care and diagnosing disease. “When you have a surgeon come up to you and say, ‘If it wasn’t for your device, I couldn’t have helped that patient,’ that’s pretty powerful,” Hergenrother said.

As the director of the new Alliance for Innovative Medical Technologies (AIMTech), Hergenrother is focused on creating the next generation of life-changing medical devices in Birmingham. AIMTech is a partnership between UAB and Southern Research Institute, modeled after the two institutions’ successful Alabama Drug Discovery Alliance. It will identify promising projects already in development at both institutions and launch new projects that meet pressing clinical needs, Hergenrother explains. AIMTech will provide investment and support to bring these projects through clinical trials and FDA approval. Then the devices will be spun off in startup companies or licensed to major medical device makers.

Scouting for the Next Big Thing

Hergenrother, who also has a faculty appointment in the UAB Department of Biomedical Engineering, is now meeting with clinicians and researchers across campus. “In one day I can go from drug delivery to sports medicine to physical therapy to radiology,” he said. “I get to see a lot of different ideas and work with people who really are excited about moving these ideas forward.”

AIMTech director Robert Hergenrother (right) and David Brown (left)
test new rehabilitation technologies in Brown's lab. AIMTech's goal
is to develop promising projects into market-ready medical devices.

Some projects are already highly developed, Hergenrother says, including high-tech rehabilitation devices created in the lab of David Brown, Ph.D., in the UAB Department of Physical Therapy. Others are simply intriguing concepts. Hergenrother recently met with a surgeon who wants to develop a new tool for cartilage repair. “He had an idea and a drawing,” Hergenrother said. “We were able to come in and make a quick prototype and put it in his hands. He was fired up. It’s a great way to just start answering questions: ‘Is this working, yes or no?’”

Conversations with UAB clinicians will lead to opportunities to create entirely new types of devices. “We want to focus on what is causing people problems now,” Hergenrother said. One of his main jobs, he explains, is to connect clinicians with researchers who can develop solutions to meet their needs.

Hergenrother, who holds 18 patents of his own, understands the thrill of a new invention. But creating a successful medical device isn’t a matter of innovation alone, he points out. As part of the initial scouting phase of the program, “I’m asking investigators to work with me to conduct 20 interviews with the people who will be the ultimate end-users of their product,” he said. “They need to find out how people are doing the job now, what the current solutions are and what advantages their product has to offer.”

Competitive Advantages

Major medical device companies are always eager for new ideas, Hergenrother says. As the industry matures — it is projected to grow by nearly 21 percent by 2016 — those companies are focusing more on international expansion and production efficiencies, he adds. “They’re relying on smaller companies and universities to drive innovation.”

Top Targets AIMTech will initially focus on developing projects in five key areas:
Cardiology
Orthopedics
Ophthalmology
Rehabilitation Engineering
Trauma

But companies aren’t as quick to make deals as they once were. In the past, “it was enough to have neat graphs and some bench data” to attract a licensing agreement with a device manufacturer, Hergenrother said. Today, the financial stakes are higher, and “companies want short- and long-term animal data, and even human data” before they are willing to invest in unproven technology.

In industry jargon, this is known as “de-risking” — building up the scientific and marketing data necessary to justify a major financial investment. AIMTech will be able to supply that proof by tapping into the combined capabilities of Southern Research and UAB.

UAB’s Institute for Innovation and Entrepreneurship (IIE) will vet the intellectual property position of every project that enters the AIMTech program. IIE and Southern Research will also evaluate potential market size, regulatory pathways and reimbursement strategies so that only the strongest, most market-ready technologies advance through AIMTech’s pipeline. Southern Research has extensive experience in assembling product-development systems and negotiating the regulatory requirements of clinical trials and FDA approvals, Hergenrother notes. “Someone has to do that work,” he said. “If we can take our projects further along than another university, ours will be more attractive to potential partners.”

AIMTech’s ultimate mission is to get life-changing products to market as quickly as possible, Hergenrother says. “We always want to keep in mind why we’re doing this. It’s not to get another patent, but to save lives. We have an opportunity to really make a difference here.”

Using magnets to find new drugs: Inside UAB's high-field nuclear magnetic resonance facility

Most 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 Facility occupies a gleaming ground-floor space in the Chemistry Building. Its massive magnets give researchers invaluable insight into disease-causing proteins — and the data they need to find new ways to stop them.

The cover story of the latest issue of UAB Magazine features the Alabama Drug Discovery Alliance, a partnership between UAB and Southern Research Institute that aims to accelerate high-potential discoveries from the lab to patient-ready treatments. One key tool in that process is the Central Alabama High Field Nuclear Magnetic Resonance Facility, which opened in 2013. The Mix takes a closer look in this new feature.

Spin This Way

Each of the facility's NMR machines specializes in a different type of job, but the basic functioning is the same, explains NMR director N. Rama Krishna, Ph.D., UAB professor in the Department of Biochemistry and Molecular Genetics. The machines generate strong magnetic fields that polarize the tiny magnets in the nuclei of hydrogen atoms. “Then, using radiofrequency pulses, you can count all of the individual hydrogen atoms in a sample, which tells you what amino acids are present and how they are arranged in space,” Krishna says. And that’s precisely the information you need to create a detailed picture of a protein’s structure.

Mapping a protein's structure is crucial to understanding its function — and to finding ways to alter that function to treat disease. For instance, locating suitable "binding pockets" on a protein linked to brain cancer tells medicinal chemists how to design a drug to block (or enhance) that protein. "That's why NMR is one of the most versatile tools for drug-discovery research," Krishna says.

The bigger your magnet, the better images you can get. The centerpiece of the NMR facility is an 850 MHz Bruker BioSpin model, one of the largest in the South, which allows scientists to analyze structural data on even the largest proteins.

(Story continues after graphic)

Building a Better Drug

The 850 MHz machine can also accelerate the drug-discovery process "by allowing researchers to rapidly test new compounds they've developed in the lab," Krishna adds. Using a technique called saturation transfer difference NMR (STD-NMR), Krishna and his team can register the minute changes in signals from hydrogen atoms that occur when a compound binds to a protein. It would be nearly impossible to capture this interaction directly, he points out, because "it may last only a few microseconds." With STD-NMR, researchers can screen a number of potential drugs at once, then focus on the ones that show signs of binding to the target protein.

UAB's Rama Krishna and scientists from Southern Research
Institute have collaborated in developing a novel high-field
NMR-based protocol for determining the binding of
allosteric ligands to target proteins. They used the kinesin-5
protein Eg5 (a cancer target) and its inhibitor monastrol
 as an example (see above) for this protocol.

Using other techniques, researchers can analyze the disease-causing interaction between two proteins, and then find the right location to dock an inhibitor that would prevent the proteins from coming together. Or they could do the opposite, in an approach dubbed “fragment-based discovery” — using NMR data to identify two compounds that bind close together on a protein and “cross link” them to significantly improve their binding.

Krishna uses these techniques in his own National Cancer Institute-funded research to find new treatments for pancreatic cancer. Other UAB investigators are using the NMR facility to further their drug-discovery efforts in Parkinson's disease, brain tumors, breast cancer, heart disease, HIV and more. And as word of these capabilities has spread, researchers at institutions across the South have begun sending in samples to the NMR facility for evaluation.

Early Warning Signs

NMR is useful for many applications beyond drug discovery, Krishna adds. The facility's 600 MHz machine specializes in a hot area of medicine known as metabolomics, which studies the way the body processes everything from food to medicines.

"If you are taking a drug that is toxic to the liver, the body will generate some small molecules — known as metabolites — associated with liver damage,” Krishna explains. "We can detect these molecules in the NMR spectra of biofluids such as urine and blood plasma and say, 'Aha, after this patient started taking the drug, we can see an increase in these signals, so something is going wrong." That can warn researchers of side effects from new drug treatments "long before there is any major problem," Krishna says.

"The range of applications in this facility is amazing," adds Krishna. "It is a unique platform for everything from basic science to translational research.”

A Parkinson's therapy makes its way through the "valley of death"

Andrew West is pursuing a compound to inhibit LRRK2, an enzyme that appears to be a central enabler
of the brain cell death seen in Parkinson's disease.

In its long journey from the petri dish to the first human patient, every new drug has to cross a wasteland called the "valley of death." Therapeutic programs enter, but most don’t come out the other side.

"The government is good at funding basic research to identify drug targets, and Big Pharma is good at taking drugs and putting them through clinical trials," says Andrew West, Ph.D., John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB. "But all of the in-between work, the pre-clinical and drug development components, is called the 'valley of death' for research, because nobody funds it, nobody pays attention to it. That's a big part of the lack of new drugs."

In fact, less than 10 percent of drugs that make it into preclinical testing will end up getting FDA approval, according to the agency's figures. But West is part of a new approach to the drug-discovery process designed to upend those odds: a partnership between UAB and Birmingham-based Southern Research Institute known as the Alabama Drug Discovery Alliance (ADDA).