(ORDO NEWS) — Scientists have discovered changes in the neurological structure that may underlie the autism spectrum disorder known as Pitt-Hopkins syndrome, thanks to laboratory-grown brains made from human cells.
In addition, researchers have been able to restore lost genetic functions using two different gene therapy strategies, hinting at the possibility of developing treatments that will one day give people with the disease new opportunities to improve their quality of life.
Pitt-Hopkins syndrome is a neurodevelopmental disorder caused by a mutation in a DNA control gene called transcription factor 4 (TCF4). Placed on the autism spectrum due to its severe effects on motor skills and sensory integration, it is a complex condition that presents with varying degrees of severity.
Moreover, changes in the TCF4 gene are associated with other forms of autism and various neurodevelopmental diseases, including schizophrenia.
Despite its obvious importance in our brain development, we know surprisingly little about how this gene works, whether in its typical or mutated form.
Researchers from the University of Campinas in Spain and the University of California San Diego (UC San Diego) set out to change that by studying how genes work in an environment as close as possible to the developing brain.
Skin cells taken from volunteers diagnosed with Pitt Hopkins syndrome were reprogrammed into stem cells that formed the basis of a brain-like mass called the cerebral cortex organoid.
Organelles are simplified versions of the real brain, unable to perform all the functions expected of a real organ. However, they are helping researchers study some aspects of the brain, demonstrating features such as the order of tissue development and the cascade of chemical triggers that we can observe in a growing fetus.
By studying the development of tissues with mutated versions of TCF4 taken from people with Pitt Hopkins syndrome and comparing them to tissues with more typical TCF4 genes, the researchers were able to map changes in tissue structure and function.
“Even without a microscope, it was possible to determine in which brain organelle the mutation occurred,” says pediatrician Alisson R. Muotri from the University of California at San Diego.
Organoids created with atypical TCF4 genes were noticeably smaller than control organoids, for example, some of them showed a polarized distortion of the overall structure.
The researchers also found that the version of the gene responsible for Pitt-Hopkins syndrome freezes the progenitor cells that give rise to different types of neurons, disrupting their ability to diversify.
This leads to a decrease in the number of neurons in the cerebral cortex, as well as a decrease in their activity – two factors that may help explain the deeper differences in the brain in autism or schizophrenia.
Part of the reason for this decrease in neuronal differentiation appears to be a decrease in a certain type of signal passing through cell membranes.
By artificially maintaining this signal with targeted pharmaceuticals, the researchers found that they were able to return at least some of the neuronal diversity and electrical activity to the cortical regions of the organoids.
Genetic correction of the TCF4 mutation in tissues also reversed the effect of the mutation, making organoids created from volunteers with Pitt-Hopkins syndrome more similar to control organoids.
“The fact that we can fix one gene and the entire neural system will recover, even at a functional level, is amazing,” says Muotri.
It’s a small, key piece of information that could one day lead to revolutionary treatments, although that day is still a long way off.”
Organoids are not fully functional brains, leaving a lot of room for overlooked factors that can complicate matters.
Moreover, diseases such as autism and schizophrenia become apparent only after birth. Without knowing how changes in nerve differentiation and activity affect the function of a more fully formed brain, it is impossible to determine the value of such treatments.
But while this is a small step towards understanding how some neurodevelopmental disorders develop, it is also a breakthrough that could give those affected by the mutated gene a choice about how to manage their health.
“For these children and their loved ones, any improvement in motor-cognitive function and quality of life is worth trying,” says Muotri.
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