In addition, researchers were able to regain lost genetic function through the use of two different gene therapy strategies, hinting at the possibility of treatments that could one day offer people with the disease new options to improve their quality of life. .
Pitt Hopkins syndrome is a neurodevelopmental condition derived from a mutation in a DNA management gene called transcription factor 4 (TCF4). Classified on the autism spectrum due to its severe impact on motor skills and sensory integration, it is a complex condition that presents a number of severities.
In addition, changes in the TCF4 gene are associated with other forms of autism and various conditions of neurological development, including schizophrenia.
Despite its clear importance in the development of our brain, we are surprised to know little about the mechanisms of the gene, neither in its typical nor mutated forms.
Researchers at the University of Campinas in Spain and the University of California at San Diego (UC San Diego) wanted to change this by studying how genes work in an environment as close to a developing brain as they could ethically achieve.
Skin cells extracted from volunteers diagnosed with Pitt Hopkins syndrome were reprogrammed into stem cells that formed the foundations of a brain-like mass called the cerebral cortical organoid.
Organoids are simplified versions of a real brain, unable to perform all the functions expected of a real organ. However, they help researchers study aspects of the brain, demonstrating features such as the order of tissue development and the cascade of chemical triggers that we might see in a growing fetus.
By studying the progression of tissues with mutated versions of TCF4 taken from individuals with Pitt Hopkins syndrome and comparing them with tissues with more typical TCF4 genes, researchers could map changes in tissue structure and function.
“Even without a microscope, you could tell which brain organoid had the mutation,” says pediatrician Alysson R. Muotri of UC San Diego.
The masses created with atypical TCF4 genes were noticeably smaller than the control organoids, on the one hand, with some showing polarized distortion in their 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, impairing their ability to diversify.
This translates into a reduction in the amount of neurons in the cortex, as well as a decrease in their activity, two factors that could help explain the deeper differences in brains with autism or schizophrenia.
Part of the cause of this drop in neuronal differentiation appears to be a drop in a specific type of signaling that occurs across cell membranes.
By artificially supporting this signal through targeted pharmaceuticals, the researchers found that they could return at least some of the neuronal diversity and electrical activity to the cortical areas of the organoids.
Genetic correction of TCF4 mutations in tissues also reversed the effects of the mutation, making organoids constructed from volunteers with Pitt Hopkins syndrome appear more similar to control organoids.
“The fact that we can correct this gene and have the whole neural system restored, even on a functional level, is amazing,” says Muotri.
It is a key piece of information that could one day lead to some revolutionary therapies, although that day is still a long way off.
Organoids are not fully functional brains, leaving plenty of room for overlooked factors that could complicate matters.
More importantly, conditions such as autism and schizophrenia only become apparent after birth. Without knowing how changes in nerve differentiation and activity affect the function of a more fully formed brain, it is impossible to know the value of therapies like these.
But while it is a small step toward understanding how some neurodevelopmental disorders develop, it is also a breakthrough that could offer those affected by the mutated gene a choice about how they manage their well-being.
“For these children and their loved ones, it would be worthwhile to try any improvement in motor cognitive function and quality of life,” says Muotri.
This research was published in Communications of nature.