12 October 2022
In a major advance for the treatment of Alzheimer’s, QIMR Berghofer scientists and collaborators have overcome a significant obstacle by successfully delivering drugs through patient cell models of the human blood-brain barrier.
The blood-brain barrier is a protective wall of cells designed to prevent pathogens and toxins from entering the brain via the blood, but it also blocks 98% of disease-fighting drugs.
By applying focused ultrasound and microbubble technology to the models grown from stem cells derived from the skin cells of Alzheimer’s patients, the team demonstrated how two promising drugs may be delivered through the barrier and into the brain safely and effectively.
Different methods and devices using focused ultrasound are currently being explored in clinical trials, indicating safety. The Queensland Brain Institute has successfully used the ultrasound technology to deliver drugs in several animal models. Now the QIMR Berghofer team’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 results have just been published in the prestigious journal Theranostics.
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.
“We found the delivery of specific drugs was significantly increased in the blood-brain barrier models using the ultrasound-microbubbles method. We also showed the treatment was safe with no damage to the cell models. The results were robust and reproducible which is really exciting.
“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,” said Dr Oikari.
QIMR Berghofer 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 U.S. Food and Drug Administration (FDA), and an anti-Tau protein RNF5, both made by the co-authors at Queensland Brain Institute.
QIMR Berghofer PhD candidate Joanna Wasielewska who co-authoured the research article, said the screening platform could offer a personalised medicine approach in the future.
“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 ten 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,” said Ms Wasielewska.
Co-author and the head of QIMR Berghofer’s Cellular & Molecular Neurodegeneration Laboratory Associate Professor Anthony White said there is no cure for Alzheimer’s disease so finding a way to improve treatment will make a huge difference to the lives of millions of patients.
“I know personally how heartbreaking this disease is after my mother passed away from Alzheimer’s 15 years ago. Even though I was working in the field, I knew there was nothing that could be done for her. It is incredibly rewarding to know that we have finally made this important advancement that 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,” said A/Prof White.
Alzheimer’s disease is the most common form of dementia. The degenerative brain disease affects memory, thinking, and physical functioning. It’s estimated nearly half a million Australians are living with dementia, with cases predicted to more than double over the next 37 years according to Dementia Australia. While more common in older Australians, younger onset dementia affects people in their 40s and 50s, and around 2,300 Australian children are living with childhood dementia.
The researchers collaborated with a number of partners on the research including leading therapeutic ultrasound expert Professor Jürgen Götz who is the Director of the Queensland Brain Institute’s Clem Jones Centre for Ageing Dementia Research (CJCADR), as well as The University of Queensland, The University of Melbourne, and The Florey Institute of Neuroscience and Mental Health.