CTSI funding accelerates four innovative translational projects through next stages

Researchers aim to integrate physical therapy into primary care, automate the next generation of surgery, solve ‘unsolvable’ flu vaccine issues, and develop epigenetic therapies for Prader-Willi syndrome

August 9, 2017

Four teams of researchers have received $150,000 to pursue translational research projects through CTSI’s Translational Accelerator Awards. The funding agreements last twelve months, and they’re designed to help quickly move innovations through intermediary stages, such as proof-of-concept, and to develop data to support larger studies in the future. 

Integrated Musculoskeletal Physical Therapy in the Patient Centered Medical Home (IMPaC)

According to Adam Goode, DPT, PhD, about 31% of all patients who come through the primary care clinic have musculoskeletal complaints. Some get referred to physical therapy on their second or third visit, so the question for this team became, “What if patients could see a physical therapist first? How would that change their outcomes?” 

The project is led by Goode, whose work in the Duke Outpatient Clinic wrestling with the issues surrounding musculoskeletal complaints inspired him to reach out to Lynn Bowlby, MD, who was working on answering similar questions at the Duke Outpatient Clinic. Now working together, the pair aim to find out if integrating physical therapists and therapy into primary care decreases cost of care, opioid prescriptions, and other issues for patients with musculoskeletal complaints.

To begin answering these questions, the research team developed a co-location model for physical therapy in primary care clinics through an observational study at Duke over the last three years.

While it is already possible to see a physical therapist without a physician referral in all fifty states, two primary insurance providers in the United States, Medicare and Medicaid, do not cover those visits without physician referral because not enough data has been gathered that supports doing so.

In the next stage of the project, supported by CTSI funding, the researchers want to build on the co-location model, developing a more integrated model of care in a multi-site clinical trial. In the integrated model, physical therapists will not only be on-site at primary care clinics, but they may play a more prominent role in the initial contact with the patient — patients with musculoskeletal complaints who come into the clinic may even see a physical therapist first.

 

Beyond Drills, Cautery, and Suction: Automating the next generation of surgery

A team led by Patrick Codd, MD, has been awarded funds to update a process that hasn’t changed since the mid-20th century: surgical tools and techniques for tumor removal. The team aims to develop a new approach to surgery that incorporates cutting-edge laser, robotics, and medical imaging technologies to allow surgeons to more precisely and delicately perform tumor removals. Codd, a full-time neurosurgeon at Duke, performs almost exclusively minimally-invasive brain tumor surgeries.

According to Codd, a lot of mysticism surrounds neurosurgery. “People get the impression that patients go into the operating room, something magic happens, and the tumor is gone,” he says. "But the truth is, we’re still using some instrumentation dating from the early 1900s. We're doing surgery carefully, under a microscope, as precisely as we possibly can, but success still comes down to the accuracy of the two human hands holding the tools."

Medical imaging has evolved so that an incredible amount of information is available to surgeons.  Within engineering, precision manufacturing and machining now allow for incredibly precise material shaping and removal.  However, the mechanical manipulations of tissue at the center of neurosurgery are still performed using surgical tool design often dating from the early 20th century.

How can tools be designed specifically for the tight, nonlinear space of the brain, and how can surgeons circumvent the natural tremors and inaccuracies of human hands? Answering those questions led Codd to concentric tube robotics: snake-like robots that can twist and curve infinitely to reach their target without needing to physically move the brain out of the way.

Last year, the team took this initiative even further to create a prototype robot that could autonomously remove tissue. However, this version is an open-loop concept, meaning that it needs feedback from the surgeon to determine whether it is performing the function accurately. A closed loop, on the other hand, would continuously receive feedback and adjust its path and depth to complete the task without needing intervention from the surgeon while also incorporating multiple medical imaging sensory streams and interlocking safety mechanisms.

The Translational Accelerator Award will be used to develop this closed-loop process and develop an image-guided, semi-autonomous surgical robot. As the tissue is eliminated, the robot will use real-time imaging strategies from spectroscopy to adjust the laser settings and complete the surgery on its own.

According to Codd, this development is possible at Duke because of strong collaborations between the School of Medicine and the Pratt School of Engineering, and this team draws on strongly multi-disciplinary backgrounds to take advantage of those collaborations.

 

Bivalent Influenza Viruses as Next-Generation Vaccines

The third project, led by Nicholas Heaton, PhD, of the Department of Molecular Genetics and Microbiology, is a continuation of the lab’s development of novel genomic organization for influenza viruses. The project may solve vaccine production problems that, until now, have been considered ‘unsolvable’ by most of the industry.

The influenza A virus causes nearly 5 million cases of severe illness and an estimated 250,000-500,000 deaths per year. Vaccination is the main strategy used for combating this virus, but the current vaccine production process has several issues. 

According to Heaton, capacity constraints mean that only the strains most likely to spread at epidemic levels are fully developed for the market — and they have to be developed quickly in order for vaccinations to take place before the flu season is at its height. If the lab responsible for predicting which strain will be relevant makes a mistake, the entire flu season could pass before a vaccine for the epidemic strain is developed. Further, vaccine strains are grown in embryonated chicken eggs, and it’s impossible to predict whether clinically-relevant strains will grow well in those conditions.

These issues have long been assumed to be unavoidable aspects of the vaccine-development process, but the lab has developed a novel way to modify the virus to incorporate two functional hemagglutinin proteins in the same vaccine. They call their new modification ‘bivalent’ viruses. Not only does the pairing of multiple hemagglutinins improve the virus’ growth in chicken eggs, it also means they could be adapted to work better in other production environments as well, solving the additional issue of developing vaccines for people with egg allergies.

This new process could allow for more stable production of vaccines and significantly reduced production costs. The next stage of the project, supported by CTSI funding, will allow the team to facilitate commercial licensing or in-house development of a marketable product.

The findings of the first stages of this project were published in the journal of the American Society for Microbiology in June 2017 as Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs.

 

Epigenetic Therapy of Prader-Willi Syndrome

The fourth project comprises a newly-forged partnership with ConduITS, the Institutes for Translational Sciences at Icahn School of Medicine at Mount Sinai. This project is lead at Duke by Yong-Hui Jiang, MD, PhD, a physician scientist with the Duke Department of Pediatrics who has spent the last ten years working with children who have Prader-Willi Syndrome (PWS). His collaborator at Mount Sinai, Jian Jin, PhD, is a chemical biologist in the Biophysics and Systems Pharmacology program.

The project is a collaborative effort to develop a novel epigenetic therapy for PWS, a genetic disorder that affects approximately 1 in 12,000 newborns. According to Jiang, this disease manifests in early feeding difficulties, childhood obesity, intellectual development issues, and behavior problems. While physicians can diagnose this condition through early genetic testing, no effective molecular therapy is available to those affected.

The researchers plan to optimize one of two compounds they have identified that shows promise in mouse models. The lead compound, UNC0642, was identified through a small molecule drug screen program in collaboration with Bryan Roth, MD, PhD.  The compound was first synthesized by Dr. Jian Jin at UNC before he began working with Mount Sinai. While UNC0642 is promising, it has not been assessed fully for safety and off-target (unintended) effects, and does not show optimal central nervous system penetration or oral bioavailability, meaning it may not be effective as an orally-administered drug.

The funding through Duke CTSI and ConduITS will allow Jin’s team at Mount Sinai to create a derivative compound that may have better central nervous system penetration, lower toxicity, and few off-target effects, while Jiang’s team at Duke will examine the derivative compound for efficacy and toxicity in mouse models of PWS and determine the optimal dose regimen of the novel therapy.


The Translational Accelerator Awards are part of Duke’s Clinical and Translational Science Award pilot project funding. They are designed to support projects through a one-year funding and project management agreement, helping researchers move innovations quickly to the next stage of development. The objective of most Translational Accelerator Award projects is not to be in the clinic after one year, but to reach a closer, specific milestone on the journey to patients.