Joseph Frank, Chief of the Frank Laboratory in Radiology and Imaging Sciences at the National Institutes of Health (NIH), recently visited the Foundation to present a webinar about his team’s work using focused ultrasound to boost stem cell homing.

joseph frankStem cells are often used in the field of regenerative medicine to help rebuild tissue that has been damaged or lost due to disease. Frank’s team has been using non-thermal pulsed FUS to direct or “home” stem cells to a particular location in the body, creating a “transient molecular zip code” – a technique that could transform regenerative medicine.

In an interview conducted in June 2015 at the Focused Ultrasound Foundation, we asked Dr. Frank about his laboratory, and work in focused ultrasound (FUS).

Q. When and how did you get interested in FUS?
A. Around 2008, I took over a laboratory on campus after the principal investigator (Dr. King Li) left NIH. The remaining staff scientist, Victor Frenkel, PhD, was involved in focused ultrasound (FUS) research. I started to look at the research that had been done and quickly realized that the molecular biological effects of FUS and US were essentially unexplored. It was clear that there were very obvious research areas that required further investigation. I went from having no background in focused ultrasound to now leading a lab where approximately 70% of our work is exploring focused ultrasound--based therapeutic approaches to improve cell therapy in treating diseases.

Q. What were you doing before then?
A. First and foremost, I’m trained in internal medicine and oncology, so my work always comes back to helping patients. In the early 1970s, I was part of the early days of MRI as a master’s student under Professor Paul Lauterbur, who won the Nobel Prize in Physiology and Medicine in 2003 for inventing MRI. I was able to do some of the first in vivo imaging in mice in this country. Since then, I’ve spent time studying the use of MRI in multiple sclerosis treatment trials as well as nanoparticle development for cell labeling

Q. What is your current research focus?
A. Cellular therapy in regenerative medicine. Can we use non-thermal, pulsed FUS (pFUS) in the cell therapy arena to help regenerate or salvage tissue that is damaged by conditions like ischemia, inflammation, and injury? Does FUS have the mechanotransductive capabilities to make tissues more hospitable to outside stem cells?

Q. What is mechanotransduction?
A. The best example is hearing, where your ear changes a mechanical property of sound to electrical stimulation and biological responses in the brain so you can interpret the sound. We’re interested in changing the ultrasound mechanical energy into a biochemical effect in the tissue. Our early research into acute kidney injury and peripheral artery disease has been promising, and we’re anxious to broaden our scope.

Frank InfographicQ. What clinical indications are on your radar?
A. Muscular dystrophy is an interesting area because of its incidence (about 1 in 3,500 male births) and potential societal gains. If we can induce the muscle tissue to engraft and grow after cell therapy, and ultimately increase muscular function in these patients, it would possibly be life-changing. However, it will take more research in order to implement clinically the techniques of pFUS coupled with cell therapies. We also want to investigate heart diseases. There’s some evidence in the literature that stem cells along with FUS, with and without microbubbles, may have a role in increasing vascularization of tissue in areas of fibrosis. Congestive heart failure, cardiomyopathy, myocardial infarction, chronic cardiac insufficiency all may be interesting areas of investigation for this combination approach of pFUS coupled with stem cells, assuming that the technology can overcome some targeting issues.

Q. What have you learned from your research thus far?
A. Our studies to date have been strictly preclinical, but they have shown some unexpected findings. We have observed mesenchymal stromal cells (MSCs), or stem cells with properties that release factors that will help treat diseases homing to pFUS treated tissues. We found that the application of pulsed FUS with stem cell infusions resulted in the cells homing to targeted muscles or kidneys. We’re creating what we’ve started to call a “transient molecular zip code,” which is a place where the cells want to go, or to where we want to deliver the cells. Building upon those findings, in an acute kidney injury model, we can actually prevent disease with the combination of FUS and MSCs better than with just MSCs alone. We also found that we can improve survival when acute injury is treated at its peak using pulsed FUS and MSCs, and we can increase stem cell homing in a muscular dystrophy model. Surprisingly, we’ve also just reported that drugs can interfere with the mechanotransductive effects of FUS.

Q. How large is your research staff/team?
A. We have 14 people right now, including post-docs, staff scientists, support staff, and students – a talented group. Saejeong Kim, PhD is a staff scientist who is working with stem cells to improve the therapeutic effects. Scott Burks, PhD, who was a post-doctoral fellow in the lab and is now a staff scientist, is spearheading a number of pFUS projects. Zsofia Kovacs, PhD is researching the molecular effects of pFUS in the brain. We recently added Kee Jang, PhD, who did his thesis exploring the effects of ultrasound on stem cells in cartilage repair and is now investigating the effects of pFUS in heart diseases. Pamela Tebebi, PhD was a young investigator at your 2014 Symposium, where she presented her pFUS and stem cell thesis work that was published this year. She is currently investigating pFUS in limb ischemia. William Tu, PhD is investigating advanced MRI techniques to study the effects of pFUS and traumatic injury in the brain. L. Christy Turtzo, MD, PhD, who just left the lab, was leading the group on the investigation of traumatic brain injury supported by the Department of Defense (DOD). We also have many post-baccalaureate students and technologists working in the lab investigating pFUS along with other stem cell and imaging projects.

Q. What are your funding sources?
A. I’m an intramural investigator, so all of my funding comes from the intramural program from the Clinical Center and National Institute of Biomedical Imaging and Bioengineering at the NIH. 

Q. What are the hurdles you’ve experienced in your research? In the field?
A. The field of FUS in regenerative medicine is wide open, and there aren’t many people doing this research. One hurdle I see will lie in the engineering and technological development. Can you reproduce results that you get using an experimental system in small animal models when you move to a clinical system and large animals? We use products from Alpinion, FUS Instruments, and Sonoblate, but our systems are experimental at this time. For the field in general, the question is where do you focus resources, specifically both time and money? From the early discovery in the 1970s to when the first clinical MR unit was built in 1981 represents a rapid expansion in a short period of time. This was a result of the advancement in computer technologies and influential companies (for example GE, Picker/Philips, Siemens) investing in the technique. Now, you have a lot of FUS companies trying to figure out what therapeutic space they want to work in. There is also greater challenge in the academic communities in securing grant money. The early grant pay lines for MRI were somewhere around 40% in the 1970s. Pay lines today are at approximately 10 percent in biomedical/technical development fields, making it more difficult to explore new areas of research.

Q. How can the Foundation help to support your efforts?
A. I think bringing awareness is essential, as well as opening the field’s eyes to exploring areas of research besides tissue ablation, oncology, and drug delivery. Thank you for broadcasting my webinar, and maybe your next international meeting could help bring together people who may have studied the biological effects of FUS to compare notes. I think this would include internists, immunologists, physicists, engineers, and radiologists, who are also trying to manipulate the tissue environment but for cancer treatment. The foundation can also work toward bringing investigators together to explore the molecular effects of FUS.

Q. What comes next?
A. In short, more research.

More Conditions
I’d like to look at acute and chronic kidney diseases, investigate rejection in organ transplantation, heart diseases, immunotherapy for the treatment of cancer, peripheral artery disease, and muscle diseases including sports/battlefield injuries along with exploring applications in the brain and spinal cord.

Expanding Parameters
Mainly limited by team bandwidth and funding, we have only investigated few pFUS sonication levels and pulse sequences, but it would be very interesting to know if we can improve upon our results by changing parameters since we now have some biomarkers from treated tissues. We also want to explore combination approaches with therapeutic ultrasound and clinically approved agents that will potentiate the FUS effects for cellular therapy. Just like we have shown we can block the mechanotransductive effects of pFUS with drugs, is there a way to enhance the pFUS effects with a drug in targeted tissues? We are also very interested in collaborating with other FUS groups in exploring the use of the techniques for cellular therapies or regenerative medicine so that we can translate this very promising adjunctive approach to the clinic.

Moving to the Clinic
We want to move to larger animal studies, especially capitalizing on Dr. Tebebi’s peripheral artery disease work, and begin translating the techniques and equipment in a clinically relevant way.

 

Key FUS Publications

Burks SR, Hancock HA, Ziadloo A, Chaudhry A, Dean DD, Gold E, Lewis BK, Frenkel V, Frank JA. Investigation of cellular and molecular responses to focused ultrasound in a mouse model. PLoS ONE 2011;6(9):e24730.

Ziadloo A, Burks S, Gold E, Lewis BK, Chaudhry A, Frenkel V, Frank JA. Enhanced homing of bone marrow stromal cells to the murine kidneys using non-invasive pulsed focused ultrasound exposure. Stem Cells 2012;30:1216-27.

Burks SR, Ziadloo A, Kim SJ, Frank JA. Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can increased through repeated applications. Stem Cells 2013;31:2551-60.

Burks SR, Nguyen BA, Tebebi PA, Ziadloo A, Kim SJ, Yeun P, Street J, Star RA, Frank JA. Pulsed focused ultrasound pretreatment improves mesenchymal stromal cell efficacy in preventing and rescuing established acute kidney injury in mice. Stem Cells 2015;33(4):1241-53.

Tebebi PA, Burks SR, Nguyen BA, Kim SJ, Turtzo LC, Venkatesah P, Frenkel V, Frank JA. Cyclooxygenase-2 or tumor necrosis factor-α inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle. Stem Cells. 2015;33(4):1173-86.

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