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Brain organoids to help identify therapies for neurodegenerative disease

8 November 2021
Appeared in BioNews 1120

Miniature brain-like structures grown in the laboratory are being used to uncover mechanisms of neurodegenerative diseases and to screen for effective treatments.

Scientists from the University of Queensland, Australia, took iPSCs (induced pluripotent stem cells) and programmed them to develop into brain cells. Previous research has shown that these artificial brain cells can spontaneously assemble into 3D brain organoids and form connections that begin normal human brain development (see BioNews 1085). In a new study, Professor Ernst Wolvetang and his team demonstrated that brain organoids also show signs of age-related neurodegeneration when kept for a long enough period.

'We have found that human brain organoids can be used to study the molecular mechanisms that drive brain ageing processes,' Professor Wolvetang said. 'This opens the way for testing many molecules that could become potential therapeutic drugs for a host of neurodegenerative diseases.'

Dr Mohammed Shaker, first author of the paper published in Ageing and Mechanisms of Disease, demonstrated that the anti-ageing protein klotho is progressively lost in ageing brain organoids. Conversely, genetically increasing klotho levels effectively suppressed markers of age-related decline in brain organoids. Dr Shaker believes that manipulating klotho levels in humans could be a promising strategy to treat Alzheimer's disease.

 'We genetically altered klotho levels to study the effects an increase in the protein would have on organoid brain cells – and found that it slowed ageing processes by 89 percent,' Dr Shaker said. '... If we can find a way to increase klotho in human brain cells, this could be beneficial in halting or slowing Alzheimer's disease.'

In a different study by the same team, first author Dr Julio Aguado Perez used stem cells from Ataxia-Telangiectasia (A-T) patients to create brain organoids and study the mechanisms underlying this genetic disorder. The research published in Ageing Cell shows that leakage of DNA from the cell nucleus is an important part of disease progression and can be neutralised by blocking a molecular pathway involved in inflammation. A-T is a rare genetic disorder characterised by inflammation, neurodegeneration and premature ageing. There is currently no cure for A-T and Dr Aguado Perez believes that 'This [research] opens up a whole new avenue for treatment options for this currently incurable condition'.

The creation of brain organoids from patient cells is a promising strategy to uncover disease-specific mechanisms and to identify treatments that are tailored to individuals. As reported by ABC News, unpublished research led by Professor Wolvetang involved taking blood samples from epilepsy patients, isolating the white blood cells and turning them into functioning human brain tissue. This allows the researchers to test the effectiveness of different combinations of anti-seizure drugs and select the drugs that are most effective for an individual. Professor Wolvetang concluded: 'Our approach, because it is personalised to the patient with the organoids… has the potential to fundamentally transform epilepsy care.'

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