In a pilot study on four patients with amyotrophic lateral sclerosis (ALS), Canadian researchers demonstrated how drug molecules that are ordinarily unable to enter the brain were able to pass through into the tissue by using focused ultrasound to temporarily disrupt the blood–brain barrier (BBB). While no treatments were tested, the study aimed to test the safety and effectiveness of the technique (Nature Commun. 10.1038/s41467-019-12426-9).
ALS, commonly known as motor neurone disease, is a degenerative disorder of the nervous system that causes widespread paralysis and eventually death. There is no cure and treatments are generally ineffective. Like many neurological diseases, such as Alzheimer’s or Parkinson’s, the development of new treatments for ALS is impeded by an inability to get potentially promising drug molecules into the brain. This is due to the existence of the BBB, a system of physical barriers and cellular mechanisms in the brain’s vascular system that prevent unwanted molecules from entering this sensitive environment.
Drugs that affect the brain, such as anaesthetics, tend to be small molecules, which can pass through the BBB. However, many new promising drugs are very large molecules, such as antibodies and gene therapies, that are kept at bay by the BBB.
The researchers, based at Sunnybrook Research Institute in Toronto, disrupted the BBB in patients using MRI-guided focused ultrasound along with microbubbles: small gas bubbles, around the same size as a red blood cell, coated with a lipid shell, which respond to ultrasound. Microbubbles can be safely injected intravenously and travel through the blood vessels. Once they reach the BBB, ultrasound is applied to make the bubbles expand and contract within the blood vessels, temporarily making them more permeable. This in turn allows drug molecules in the blood to pass through into the brain tissue. The team monitored the whole process using the MRI scanner.
Focused ultrasound is much less invasive than the most effective alternative for drug delivery: directly injecting drugs into brain tissue, which requires opening up the skull. The approach also enables the BBB to be opened in a variety of regions. The phenomenon was first discovered in rabbits around 20 years ago, and a number of early clinical trials have taken place in the last five years. The Sunnybrook group has previously performed similar trials to open up the BBB in patients with Alzheimer’s disease and aggressive brain tumours.
The team used a commercial ultrasound system containing 1024 transducers embedded in a helmet that is placed within an MRI scanner. To reduce the chance of adverse effects and ensure the sound pressures used were correct, the researchers monitored the therapy in real time by detecting the ultrasound emitted by the bubbles, and by monitoring the temperature inside the brain using the MRI scan. The study did not test the efficacy of drug treatments, but instead used a gadolinium-based contrast agent that showed up within the brain tissue on the MRI.
The patients reported no serious adverse side effects beyond headaches and mild pain. One participant showed slight structural changes on the MRI scan that were not associated with any symptoms and had disappeared in a scan a week later. The BBB closed within 24 hours.
While this study didn’t test any drugs and was not aiming to treat the patients, it demonstrated that the approach works and appears safe. The team now aims to move on to delivering drugs using this technique, opening up a path towards more effective treatments for ALS.