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Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations
Delaney G Fisher1, Tanya Cruz1, Matthew R Hoch1
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
Abstract:
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.
Insights
Pulsed, low-intensity, focused ultrasound-microbubble (FUS-MB) treatment safely halts cerebral cavernous malformation (CCM) growth in mice. This minimally invasive approach also reduced new CCM formation, offering potential for future patient therapies.
Area of Science:
- Neuroscience
- Vascular Biology
- Medical Imaging and Therapeutics
Background:
- Cerebral cavernous malformations (CCMs) are CNS vascular lesions causing neurological symptoms.
- Current treatments like surgery and radiosurgery carry risks for some patients.
- A Krit1 null murine model closely represents human CCM pathology.
Purpose of the Study:
- To evaluate pulsed, low-intensity, focused ultrasound-microbubble (FUS-MB) treatment efficacy in a murine CCM model.
- To assess FUS-MB's ability to control CCM growth and prevent new lesion formation.
Main Methods:
- FUS-MB treatments were guided by magnetic resonance imaging (MRI) in Krit1 null mice.
- Blood-brain barrier permeability was assessed using gadolinium contrast agent deposition.
- Longitudinal MRI tracked CCM volume changes and lesion formation over time.
Main Results:
- FUS-MB treatment halted growth in 94% of treated CCMs after one month; untreated CCMs grew sevenfold.
- Treated CCMs showed a significant reduction in Krit1 null endothelial cells.
- Multiple FUS-MB treatments reduced de novo CCM formation by 81%, demonstrating a prophylactic effect.
Conclusions:
- FUS-MB is a potentially safe and minimally invasive therapeutic modality for CCMs.
- The treatment effectively arrests CCM growth and prevents new lesion development in mice.
- Further clinical trials are warranted to establish FUS-MB safety and efficacy in human patients.
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