Summary: A new, noninvasive technique using focused ultrasound and microbubbles has halted the growth of cerebral cavernous malformations (CCMs) in mice, offering hope for safer treatment options. CCMs are abnormal clusters of blood vessels in the brain that can cause serious symptoms, often treated with risky surgery or radiation.
In preclinical studies, the ultrasound-microbubble method stopped 94% of lesion growth without drugs, surgery, or radiation. This breakthrough could transform treatment for patients with familial CCMs and other high-risk cases, with clinical trials on the horizon.
Key Facts:
- Drug-Free Treatment: Focused ultrasound with microbubbles stabilized CCMs without medications.
- Impressive Results: Growth halted in 94% of brain lesions in preclinical models.
- Surgical Alternative: The approach may offer a safer, incision-free option for hard-to-reach CCMs.
Source: University of Virginia
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,” said researcher Richard J. Price, PhD, co-director of UVA Health’s Focused Ultrasound Cancer Immunotherapy Center.
“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.”
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.”
Funding: 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.
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.
About this neurology and neurotech research news
Author: Josh Barney
Source: University of Virginia
Contact: Josh Barney – University of Virginia
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations” by Richard J. Price et al. Nature Biomedical Engineering
Abstract
Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations
Cerebral cavernous malformations (CCMs) are vascular lesions within the central nervous system that cause debilitating neurological symptoms.
Currently, surgical excision and stereotactic radiosurgery, the primary treatment options, pose risks to some patients.
Here we tested whether pulsed, low intensity, focused ultrasound-microbubble (FUS-MB) treatments control CCM growth and formation in a clinically representative Krit1 null murine model.
FUS-MB under magnetic resonance imaging (MRI) guidance opened the blood–brain barrier, with gadolinium contrast agent deposition most evident at perilesional boundaries.
Longitudinal MRI revealed that, at 1 month after treatment, FUS-MB halted the growth of 94% of treated CCMs. In contrast, untreated CCMs grew ~7-fold in volume. FUS-MB-treated CCMs exhibited a marked reduction in Krit1 null endothelial cells.
In mice receiving multiple FUS-MB treatments with fixed peak-negative pressures, de novo CCM formation was reduced by 81%, indicating a prophylactic effect.
Our findings support FUS-MB as a minimally invasive treatment modality that can safely arrest murine CCM growth and prevent de novo CCM formation in mice.
If proven safe and effective in clinical trials, FUS-MB treatment may enhance therapeutic options for CCM patients.
