Brain organoids target rare neurological disorder

Scientists have devised a potential therapy for a rare neurological disease using brain tissue derived from human stem cells, raising hopes that so-called organoid technology can target other untreatable conditions.

Stanford University researchers changed the effect of a gene to stop it causing Timothy syndrome, whose symptoms include life-threatening heart defects, autism and epilepsy.

The results promise to boost long-standing efforts to find ­treatments for other debilitating brain conditions such as epilepsy and schizophrenia.

“It’s a new paradigm in how to understand these conditions and develop drugs,” said Sergiu Pașca, project leader and Stanford’s professor of psychiatry and behavioural sciences. “It opens of the possibility of testing other disorders in a very similar way.”

The researchers transplanted so-called brain organoids derived from the stem cells of Timothy syndrome sufferers into the brains of young rats, according to results published in Nature on Wednesday. As the rodents matured, the organoids grew and integrated into their brains.  

The scientists then targeted the action of a gene known as CACNA1C, which causes a mutation fundamental to Timothy syndrome. The gene encodes the protein building blocks of a channel through which calcium metal ions flow inside nerve cells. By introducing short strands of nucleic acids, the researchers successfully manipulated CACNA1C to produce a form of the calcium channel free from the mutation.

The researchers were now aiming to recruit sufferers of Timothy syndrome for a trial of the therapy candidate, Pașca said. The condition is thought to be a very rare condition, with only a few dozen cases reported worldwide.

Brain organoid technology is powerful because it is three-dimensional and allows biological cells to interact with their surroundings in living organisms. The technique offers better visualisation of brain structures than 2D models that lack sensory input — a key factor for brain learning.

The latest Nature study was a “great demonstration of the power of organoids for not only modelling human disease, but even developing effective therapies”, said Professor Madeline Lancaster, a leading researcher in the organoid field.

“Because organoids can be made from human cells, they can model aspects of human biology that cannot be captured in animal testing,” said Lancaster, group leader at the UK Medical Research Council Laboratory of Molecular Biology, who was not involved in the research. “They therefore offer a complementary approach to existing tools, and provide confidence that a given therapy . . . will work in the human context.”

The Nature study was likely to be the first of many to use organoids to generate more precise medications, added Lancaster, who in 2011 created the world’s first brain organoid.

With clinical trials of potential treatments for nervous system conditions suffering from high failure rates, organoids could play a particularly important role in drug discovery. They could offer a form of triage to ensure that only the best candidates go forward for tests in humans.

“The development of models that can better replicate human diseases and accurately predict human responses promises to improve the outcomes of drug-development programmes,” said Silvia Velasco, an associate professor in developmental neurobiology at Australia’s Murdoch Children’s Research Institute, in a commentary also published in Nature.

“As shown by the current study, stem cell-based models are well suited for validating drug targets, and for screening and optimising drug candidates.”