The lab-grown brains were developed from human cells and could be used to uncover changes in neurological structure that could underlie the disorder.
The researchers were able to recover lost genetic functions through the use of two different gene therapy strategies, suggesting the possibility of treatments that could one day give those with the condition new options in improving their quality of life.
There is a genetic condition called PittHopkins syndrome, which is caused by a deficiency in the transcription factor 4. It is a complex condition that presents with a range of severities due to its severe impact on motor skills and sensory integration.
Alterations in the TCF4 gene are associated with a variety of conditions, including schizophrenia.
In spite of its significance in our brain, we don't know much about the gene's mechanisms.
Researchers from the University of Campinas in Spain and the University of California San Diego wanted to change this by studying the workings of the genes in an environment as close to a developing brain as they could ethically get.
Stem cells from skin cells taken from people with Pitt Hopkins syndrome formed a brain-like mass called a brain cortical organoid.
Organoids can't perform all of the functions expected of an actual organ. They help researchers study aspects of the brain, such as the order of tissue development, and the cascade of chemical triggering in a growing fetus.
By studying the progress of tissues with different versions of TCF4 taken from people with Pitt Hopkins syndrome, the researchers could map changes in the structure and operation of the tissues.
Even without a microscope, you could tell which brain organoid had a particular abnormality.
The mass created with atypical TCF4 genes were noticeably smaller than the control organoids, with some showing a distortion in their general structure.
The progenitor cells that give rise to different types of neuron can be stopped by the version of the gene responsible for Pitt Hopkins syndrome.
The reduction in the amount of neurons in the cortex and a drop in their activity could be related to this.
There is a drop in a specific type of signaling that occurs across cell membranes that is part of the reason for the drop in neural differentiation.
The researchers found that by artificially supporting this signal through targeted pharmaceuticals, they could return some of the neural diversity and electrical activity to the cortical areas of the organoids.
The organoids constructed from volunteers with Pitt Hopkins syndrome look more similar to control organoids because of the genetic correction of the TCF4 mutations in the tissues.
Muotri says the fact that we can correct this one gene and the entire neural system reestablish itself, even at a functional level, is amazing.
It is a small piece of information that could lead to some revolutionary therapies one day.
Organoids aren't fully functional brains, leaving plenty of room for overlooked factors that could complicate matters
After birth, conditions such as autism and schizophrenia can be seen. Without knowing how changes in the activity of the nerves affect the function of a fully formed brain, it is impossible to know the value of therapies like these.
It is a small step towards understanding how some neurodevelopmental disorders unfold, but it is also a breakthrough that could give those affected by the mutated gene a choice in how they manage their wellbeing.
For these children and their loved ones, any improvements in motor-cognitive function and quality of life would be worth the try.
Nature Communications published this research.
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