Key considerations for clinical translation
The complexity of the brain
The inherent complexity of brain anatomy presents challenges for ultrasound-based delivery and drug development in general. Each region of the brain has distinct vascular architecture, cellular composition, and barrier properties, meaning different ultrasound parameters may be required for optimal results. For instance, studies in macaques have shown that settings sufficient to open the BBB in grey matter were ineffective in white matter. These insights are allowing us to steadily improve our dosing strategies. In humans, cavitation dose prescriptions are already dependent on the target area, with higher doses for the hippocampus and lower doses for regions such as the thalamus, parietal and frontal lobes.
Moreover, our understanding of brain physiology continues to evolve. A recent discovery revealed a fluid network running alongside cerebral veins, suggesting a natural drainage system previously unknown. Encouragingly, targeting the hippocampus appears to yield more consistent results than other regions. As our understanding advances, we can only expect the efficacy and reproducibility of treatments to improve.
Safety concerns
Safety remains a central concern in ultrasound-mediated BBB disruption. Excessive exposure can lead to serious adverse effects, including vascular rupture and haemorrhage, ischemia due to vasoconstriction, cerebral oedema, inflammation and direct cellular injury.
Safety outcomes are influenced by multiple variables, such as microbubble type and dosage, transducer frequency, peak-negative pressure, pulse characteristics and treatment schedules, therefore maximising therapeutic benefit must be balanced against minimising harm. Long-term patient safety information is still lacking, which will be essential for regulatory approval. Notably, clinical trials to date have reported minimal adverse events.
Measurements and monitoring
FUS requires real-time monitoring of cavitation activity and precise control over transducer elements sometimes numbering over 1,000. This technical complexity is compounded by the difficulty of focusing ultrasound through the skull, which introduces distortion and attenuation. Patient-to-patient variability further complicates targeting, making it essential to confirm that the intended brain region is receiving adequate treatment while avoiding off-target effects.
Insightec’s Exablate Neuro demonstrates that it is possible to reach the intended target region while sparing surrounding tissues. The technical sophistication necessary for FUS is now a strength of the modality as it provides confidence in treatment outcomes.
Drug delivery considerations
Delivering drugs to the brain continues to be challenging, the brain’s immunoprivileged status, along with its distinct vascular and cellular environment, means that compounds effective elsewhere in the body may behave unpredictably once delivered across the BBB.
Preclinical models often fail to fully capture human neurobiology, which has historically limited translational success and drug distribution. This is further influenced by clearance rates (both of drugs and microbubbles), regional vascular differences and patient-to-patient variability in timing. On top of this, inherent drug properties such as molecular weight, charge, lipophilicity and carrier affinity remain critical factors affecting uptake efficiency. In many cases, more demanding compounds may require higher ultrasound energy or carefully tuned parameters to open up the BBB enough to reach therapeutic concentrations in the target region.
That said, these challenges also create opportunities. As the current therapeutic toolkit for brain delivery is so limited, even modest gains could represent great clinical progress. Such advances have included optimising dosing schedules, exploiting drug properties already favourable to uptake and identifying compounds that are naturally more compatible with ultrasound-mediated delivery. These “low-hanging fruit” strategies may provide near-term wins, while longer-term efforts continue to address the more complex issues of drug design and translation.
The regulatory pathway for ultrasound-mediated drug delivery
The regulatory landscape for ultrasound-mediated drug delivery to the brain remains nascent and fragmented. While the FDA has approved focused ultrasound for certain ablation procedures, the pathway for BBB disruption combined with therapeutic delivery is still being defined. There are no standardised protocols for ultrasound parameters, microbubble formulations or treatment regimens. This lack of harmonisation makes it difficult for regulatory bodies to assess safety and efficacy across different studies, complicating efforts to establish an approval pathway.
However, there are approximately 35 clinical trials investigating the opening of the blood-brain barrier using ultrasound, with 11 completed and 24 ongoing as of mid-2024. Standardised protocols will likely emerge from these clinical trials as the field will soon begin to establish best practices.
