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Scientists have developed a potential treatment for a rare neurological disorder using brain tissue derived from human stem cells, raising hopes that so-called organoid technology can also target other untreatable diseases.
Researchers at Stanford University altered the action of a gene to prevent it from causing Timothy syndrome, whose symptoms include life-threatening heart defects, autism and epilepsy.
The findings promise to advance long-standing efforts to find treatments for other debilitating brain disorders such as epilepsy and schizophrenia.
“It’s a new paradigm for understanding these diseases and developing drugs,” said Sergiu Pașca, project leader and Stanford professor of psychiatry and behavioral sciences. “It opens up the possibility of testing other diseases in a very similar way.”
According to the results published Wednesday in Nature, the researchers transplanted so-called brain organoids derived from the stem cells of Timothy syndrome patients into the brains of young rats. As the rodents matured, the organoids grew and integrated into their brains.
The scientists then targeted the effect of a gene called CACNA1C, which causes a mutation fundamental to Timothy syndrome. The gene codes for the protein building blocks of a channel through which calcium metal ions flow into the interior of nerve cells. By introducing short strands of nucleic acid, the researchers were able to successfully manipulate CACNA1C to create a form of the calcium channel that is free of the mutation.
The aim of the researchers is now to recruit patients with Timothy syndrome to test the therapy candidate, said Pașca. The disease is believed to be a very rare disease; Only a few dozen cases have been reported worldwide.
Brain organoid technology is powerful because it is three-dimensional and allows biological cells to interact with their environment in living organisms. The technique provides better visualization of brain structures than 2D models without sensory input – a key factor in brain learning.
The latest Nature study is a “great demonstration of the power of organoids to not only model human diseases but even develop effective therapies,” said Professor Madeline Lancaster, a leading researcher in the field of organoids.
“Because organoids can be made from human cells, they can model aspects of human biology that cannot be captured in animal studies,” said Lancaster, a group leader at the UK Medical Research Council’s 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 particular therapy…” . . will work in a human context.”
The Nature study was likely the first of many to use organoids to make more precise drugs, added Lancaster, who developed the world’s first brain organoid in 2011.
Because clinical trials of potential treatments for nervous system diseases have a high failure rate, organoids could play a particularly important role in drug development. They could offer some form of triage to ensure only the best candidates are approved for human testing.
“Developing models that can better replicate human diseases and more accurately predict human responses holds promise for improving the outcomes of drug development programs,” said Silvia Velasco, associate professor of developmental neurobiology at Australia’s Murdoch Children’s Research Institute, in a commentary also published in the Nature.
“As the current study shows, stem cell-based models are well suited to validating drug targets as well as screening and optimizing drug candidates.”