Breakthrough for drug delivery through blood–brain barrier

In a major advance for the treatment of Alzheimer’s, Australian scientists have overcome a significant obstacle by successfully delivering drugs through patient cell models of the human blood–brain barrier — a protective wall of cells that is designed to prevent pathogens and toxins from entering the brain via the blood, but also blocks 98% of disease-fighting drugs. Their results have been published in the journal Theranostics.

By applying focused ultrasound and microbubble technology to the models grown from stem cells derived from the skin cells of Alzheimer’s patients, researchers from the QIMR Berghofer Medical Research Institute demonstrated how two promising drugs may be delivered through the barrier and into the brain. The Queensland Brain Institute has already used focused ultrasound technology to deliver drugs in several animal models, but QIMR Berghofer’s success in penetrating drugs through patient-derived human cell models is an advance that could transform the treatment of Alzheimer’s disease and other brain disorders.

The researchers used cells of patients with a high risk of sporadic Alzheimer’s, which causes 95% of cases in people over the age of 65 years. They tested two Alzheimer’s drugs — an analogue of aducanumab, which has been approved by the US FDA, and the anti-tau protein RNF5 — both developed at the Queensland Brain Institute.

QIMR Berghofer stem cell researcher Dr Lotta Oikari said the cell models reflect key characteristics and variations of Alzheimer’s, creating a disease-specific screening platform which promises a future of tailored treatments for individuals. She explained, “Alzheimer’s disease presents differently in each patient, and it also disrupts the blood–brain barrier itself and the way drugs are metabolised. Our models reflect those differences because the cells are derived from patients with a high risk of developing Alzheimer’s. It means this research could be more easily translated to the clinic to help patients.

“We found the delivery of specific drugs was significantly increased in the blood–brain barrier models using the ultrasound-microbubbles method,” Oikari said. “We also showed the treatment was safe with no damage to the cell models. The results were robust and reproducible, which is really exciting.”

QIMR Berghofer PhD candidate Joanna Wasielewska, who co-authored the study, said the screening platform could offer a personalised medicine approach in the future, stating, “In a decade we could eventually be at a stage where we take cells from patients, perform drug screening and then two weeks later we know which drug to give to patients. That is the goal with this work.

“It took us three years to develop this platform as we had to do everything manually. We’re now investigating how to automate the process so that we could make it 10 times faster. We could then test many more drugs using cells from more patients in a much shorter time; this could significantly accelerate Alzheimer’s disease drug discovery.”

Co-author Associate Professor Anthony White, Head of QIMR Berghofer’s Cellular & Molecular Neurodegeneration Laboratory, said it was “incredibly rewarding” to know that this important advance could help so many people.

“The cell-based screening platform we’ve created can also be adapted for other brain diseases to find new drugs and test for specific effects on patients. We are already developing models for motor neurone disease and childhood dementia,” he said.

Image caption: The cobblestone pattern of connection formed by the main type of blood–brain barrier cells, iBECs, when cultured in a 2D plate.

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