This image shows a brain “assembly” made up of two connected brain “organoids.” Scientists studying these structures have restored damaged brain cells in patients with Timothy syndrome.
Pasqua Lab, Stanford University
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Pasqua Lab, Stanford University
This image shows a brain “assembly” made up of two connected brain “organoids.” Scientists studying these structures have restored damaged brain cells in Timothy syndrome patients.
Pasqua Lab, Stanford University
Scientists have discovered a way to restore brain cells damaged by a rare and life-threatening genetic disease. timothy syndrome.
a type of drug known as antisense oligonucleotide Researchers have announced that they have enabled clusters of neurons in humans to develop normally despite carrying the mutation that causes Timothy syndrome. report in a diary Nature.
This approach could help researchers develop treatments for other genetic disorders, including those that cause schizophrenia, epilepsy, ADHD, and autism spectrum disorders.
“Now that we have the tools, it’s very exciting,” he says. Dr. Serge PasquatProfessor of Psychiatry and Behavioral Sciences at Stanford University and senior author of the study.
“This is the beginning of a new era for many of these diseases that were initially thought to be untreatable,” he says. Dr Huda Zoghbia professor at Baylor College of Medicine, was not involved in the study.
However, most of these conditions involve multiple genes rather than just one, and scientists do not know enough about these multiple genetic diseases to be able to effectively treat them with antisense oligonucleotides. Zoghbi says he doesn’t have one yet.
Insights from rare diseases
Fewer than 100 people worldwide have been diagnosed with Timothy syndrome. Children born with the disease often have heart problems, autism, epilepsy, developmental delays, and intellectual disabilities.
But because Timothy syndrome is caused by mutations in a single gene, it gives scientists a way to study changes that affect brain development.
“Rare syndromes that are genetically very well defined are like windows, or Rosetta stones, into understanding other more common conditions,” Pasca says.
So Professor Paska has spent the past 15 years studying how the mutations that cause Timothy syndrome change brain cells.
First, he and his team used skin cells from patients with Timothy syndrome to grow neurons in a dish with the mutation. The team then moved on to studying mutations in brain organoids, living clusters of human neurons that assemble into structures that resemble certain types of brain tissue.
Paska’s team then created a brain “collectoid” containing several organoids that form connections and interact, much like regions of the developing brain.
Then, in 2022, the researchers transplanted human organoids carrying the Timothy syndrome mutation into the brains of newborn rats. This allowed human cells to continue developing much longer than if they were cultured in a dish.
Repair each cell one by one
All these experiments allowed Paska’s team to understand in detail how Timothy syndrome affects brain cells.
The mutation occurs in a gene called CACNA1C, which is involved in controlling the flow of calcium ions into and out of cells. This “calcium signaling” controls many of the processes that cells need to function.
Paska’s lab showed that neurons with the Timothy syndrome mutation remain abnormally small and have a reduced ability to form connections. Certain mutant neurons were also impaired in their ability to migrate from one area of the brain to another during development.
“We basically cataloged all these anomalies,” Paska said. “And at some point, we had enough information about the disease that the treatment became obvious.”
This approach meant developing antisense nucleotides, small pieces of synthetic genetic material that modify the proteins made by cells. Antisense nucleotides for Timothy syndrome are designed to replace the defective protein with a healthy protein, effectively counteracting the mutation that causes the disease.
To see if antisense drugs were effective, Pasca’s team conducted experiments on newborn rats. First, brain organoids containing the Timothy syndrome mutation were transplanted into the cerebral cortex of rats.
As the organoids grew, they began to develop the same defects seen in the brains of people with Timothy.
Next, the researchers injected the antisense drug into the rats’ nervous systems.
“Within a few days, we will start relieving or repairing all the deficiencies that we have observed over the years,” Pasca says.
The neurons in the organoids grew larger and formed more connections. The cells also migrated normally and showed electrical activity, indicating that the calcium signaling system was functioning properly.
From rats to humans?
Pasca’s lab hopes to test the antisense drug in patients with Timothy syndrome in the next few years.
We are also studying how calcium signaling, a cellular process affected in Timothy syndrome, plays a role in more common conditions such as schizophrenia, bipolar disorder, and autism spectrum disorders. ing.
Meanwhile, scientists are working to develop antisense drugs for other rare genetic diseases that affect brain development.These include: angelman syndrome and Dravet syndrome.
Antisense drug for spinal muscular atrophy, a genetic disease that affects muscle strength approved Approved by the Food and Drug Administration in 2016.
All of these symptoms are caused by mutations in a single gene. Developing antisense treatments for conditions that involve multiple genes, such as most autism, schizophrenia and epilepsy, is likely to be much more difficult, Zoghbi says.
Still, she says there is reason to believe that scientists are now closer to a treatment strategy for these diseases.
In 1985, Zoghbi left his practice as a pediatric neurologist to conduct research because he had “nothing to offer” patients with serious genetic disorders, including: rett syndrome and spinocerebellar ataxia. “We didn’t know the cause of the disease,” she says.
Scientists now understand the genetic changes that cause hundreds of childhood conditions and have begun to develop treatments for some diseases, such as Timothy syndrome.
“It’s a dream come true for me,” Zogbi says.
