Revolutionary incision-free technique halts growth of brain cavernomas

A new, incision-free technique developed at UVA Health to treat debilitating brain lesions called cerebral cavernous malformations, or cavernomas, has shown great promise in early testing, halting the growth of the lesions almost entirely.

The new approach could represent a paradigm shift in how the malformations, commonly called CCMs, are treated, the researchers say. The technique uses tiny, gas-filled "microbubbles" propelled by focused sound waves to open the brain's protective barrier and stunt the growth of the malformations.

This is a clear example of serendipity in science. We were looking for something else – performing long-term safety studies of focused ultrasound as a tool for drug and gene delivery to CCMs – when we noticed that CCMs exposed to just focused ultrasound with microbubbles were being stabilized. After the initial observations, we spent years doing experiments to confirm the effect was real and reproducible. Because the focused ultrasound treatment is relatively simple and non-invasive and the necessary clinical devices are becoming more common, if proven safe in clinical trials, I am hopeful it could eventually become a real treatment option." 

Richard J. Price, PhD, researcher, co-director of UVA Health's Focused Ultrasound Cancer Immunotherapy Center

About cavernomas

Cavernomas are clusters of overgrown blood vessels that can sprout like weeds in the brain, spinal cord or other parts of the body. Most cases cause no symptoms, but they can, in some instances, cause headaches, seizures, muscle weakness and even death. Treatment options for patients include brain surgery, often used when the CCM is at risk of causing a dangerous brain bleed, or stereotactic radiosurgery, which uses radiation to destroy CCMs that are difficult or impossible for a surgeon to reach.

UVA's new approach could offer an alternative that avoids unwanted side effects associated with brain surgery and stereotactic radiosurgery, Price says. For example, traditional brain surgery comes with the risks of the surgery itself and also the possibility that the removed cavernomas could regrow.

Price and his collaborators were shocked at how well their microbubble treatment performed in lab tests. One month after treatment, the approach had halted the growth of 94% of CCMs in lab mice. During this same time, untreated CCMs grew seven-fold. 

"One thing that really stands out is the magnitude of the effect. The mouse models of CCM are much more severe than human CCMs. Mouse CCMs grow exponentially. Yet despite their aggressive nature, CCMs in mice still respond completely to treatment," said Price, of UVA's Department of Biomedical Engineering. "In some studies, we even saw that brain tissue exposed to focused ultrasound with microbubbles was less inclined to harbor new CCMs in the future. If translated to humans, this prophylactic effect could open the door to treatments for so-called 'familial' patients who are genetically predisposed to acquiring multiple new CCMs throughout their lifespan."

Further, simulated treatment plans for patients with CCMs (patients who have received stereotactic radiosurgery) revealed that the approach is already viable with existing technology, though clinical trials will be needed before the federal Food and Drug Administration would consider making it available for patients.

One notable aspect of the approach is that it doesn't involve the use of any drugs. Scientists at UVA and elsewhere have been exploring the potential of focused ultrasound to briefly breach the blood-brain barrier – the brain's natural defenses – to allow the targeted delivery of medications for Alzheimer's and other conditions. But in both Alzheimer's and now cavernomas, the use of the sound-propelled microbubbles appears to have dramatic benefits even without drugs – benefits scientists can't fully explain.

The promising Alzheimer's results have already led to the launch of several clinical trials testing the approach in patients. Price hopes UVA's pioneering research will prompt the launch of similar trials soon for CCMs.

"We are very interested in understanding what is in the 'black box' that somehow connects focused ultrasound to the cessation of mutant cell expansion in the CCMs. We are also returning to our original ideas about drug and gene delivery to CCMs. Since the baseline effect stabilizes the lesions, perhaps we can now think of eradicating them entirely with additional therapies," Price said. "This type of discovery is largely an outcome of the investments UVA has made in focused ultrasound technology over the years. There are few other institutions in the world with the critical mass of expertise and infrastructure to allow new discoveries like this."

Price and his collaborator Petr Tvrdik, PhD, recently received more than $3 million from the National Institutes of Health's National Cancer Institute to support their ongoing CCM research.

About focused ultrasound

UVA Health was one of the earliest pioneers in the field of focused ultrasound. UVA's expertise with the technology has led to a robust research program examining the use of focused ultrasound to treat many different conditions.

The tremendous promise of focused ultrasound prompted UVA Health and the Charlottesville-based Focused Ultrasound Foundation to launch the Focused Ultrasound Cancer Immunotherapy Center, the world's first center dedicated specifically to advancing a focused ultrasound and cancer immunotherapy treatment approach that could revolutionize cancer care for the 21st century. 

Findings published

Price and his collaborators have described their CCM results in Nature Biomedical Engineering. The research team consisted of Delaney G. Fisher, Tanya Cruz, Matthew R. Hoch, Khadijeh A. Sharifi, Ishaan M. Shah, Catherine M. Gorick, Victoria R. Breza, Anna C. Debski, Joshua D. Samuels, Jason P. Sheehan, David Schlesinger, David Moore, James W. Mandell, John R. Lukens, G. Wilson Miller, Petr Tvrdik and Price.

The study was supported by the National Institutes of Health, grants R01CA279134, R01EB030409, R01EB030744, R21NS118278, R21NS116431 and R01CA226899; the American Heart Association, grant 830909; and by the Focused Ultrasound Foundation, Be Brave for Life Foundation and the Alliance to Cure Cavernous Malformation.

UVA's Department of Biomedical Engineering is a joint program of the School of Medicine and School of Engineering and Applied Science.