This image shows a brain “assembloid” composed of two connected brain “organoids.” Scientists studying these structures have restored damaged brain cells in patients with Timothy syndrome.
Pasca Laboratory, Stanford University
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Pasca Laboratory, Stanford University
This image shows a brain “assembloid” composed of two connected brain “organoids.” Scientists studying these structures have restored damaged brain cells in patients with Timothy syndrome.
Pasca Laboratory, Stanford University
Scientists have found a way to restore brain cells damaged by a rare and potentially fatal genetic disorder called Timothy syndrome.
A type of drug known as an antisense oligonucleotide allowed groups of human neurons to develop normally even though they carried the mutation that causes Timothy syndrome, a team reports in the journal Nature.
This approach could help researchers develop treatments for other genetic diseases, including those that cause schizophrenia, epilepsy, ADHD and autism spectrum disorders.
“This is extremely exciting because we now have the tools we need,” says Dr. Sergiu Pasca, professor of psychiatry and behavioral sciences at Stanford University and lead author of the study.
“This is the beginning of a new era for many of these diseases that we initially thought were incurable,” says Dr. Huda Zoghbi, a professor at Baylor College of Medicine who was not involved in the research.
But most of these conditions involve multiple genes, not just one — and scientists don’t yet know enough about these multiple genetic disorders to treat them effectively with antisense oligonucleotides, Zoghbi says.
Insights into a rare disease
Timothy syndrome has been diagnosed in fewer than 100 people worldwide. Children born with this condition often suffer from heart problems, autism, epilepsy, developmental delay and intellectual disability.
But because Timothy syndrome is caused by a mutation in a single gene, it offers scientists a way to study changes that affect brain development.
“Rare syndromes that are very clearly defined genetically are sort of windows, or Rosetta stones, into understanding other, more common conditions,” says Pasca.
So Pasca has spent the last 15 years learning how the mutation that causes Timothy syndrome changes brain cells.
First, he and his team used skin cells from patients with Timothy syndrome to grow neurons in a dish carrying the mutation. The team then studied the mutation of brain organoids – living clusters of human neurons that assemble into structures that resemble specific types of brain tissue.
Next, Pasca’s team created brain “assembloids,” which involve multiple organoids that form connections and interact, much like areas of a developing brain do.
And in 2022, the team transplanted human organoids carrying the Timothy syndrome mutation into the brains of newborn rats. This allowed human cells to continue growing much longer than in a dish.
Repair every cell
All of these experiments allowed Pasca’s team to gain a detailed understanding of 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” in turn controls many of the processes a cell needs to function.
Pasca’s lab showed that neurons carrying the Timothy syndrome mutation remained abnormally small and were less able to make connections. Some mutated neurons also had an impaired ability to migrate from one area of the brain to another during development.
“We basically cataloged all these anomalies,” says Pasca. “And at some point, we gathered enough information about the disease that a therapeutic approach became obvious.”
The approach was to develop an antisense nucleotide, a small piece of synthetic genetic material that changes the proteins a cell makes. The Timothy syndrome antisense nucleotide was designed to replace a faulty protein with a healthy version, thereby neutralizing the mutation that causes the disorder.
To see if the antisense drug worked, Pasca’s team performed an experiment on newborn rats. First, they transplanted brain organoids containing the Timothy syndrome mutation 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 team injected the antisense drug into the rats’ nervous systems.
“Within a few days, you start to save or restore all the defects that we’ve seen over the years,” says Pasca.
The organoids’ neurons grew larger and formed more connections. The cells also migrated normally and had electrical activity indicating that the calcium signaling system was working properly.
From rats to humans?
Pasca’s lab hopes to test the antisense drug in people with Timothy syndrome over the next few years.
He also studies how calcium signaling – the cellular process affected in Timothy syndrome – may play a role in much more common conditions, including schizophrenia, bipolar disorder and autism spectrum disorder.
Meanwhile, scientists are working on antisense drugs for other rare genetic diseases that affect brain development. These include Angelman syndrome and Dravet syndrome.
An antisense drug for spinal muscular atrophy, a genetic disease that affects muscle strength, was approved by the Food and Drug Administration in 2016.
All of these conditions are caused by mutations in a single gene. Antisense treatments for conditions involving multiple genes – such as most forms of autism, schizophrenia and epilepsy – will likely be much more difficult to develop, Zoghbi says.
Still, she says, there is now reason to believe that scientists are getting closer to finding strategies to treat these diseases.
In 1985, Zoghbi left his practice as a pediatric neurologist to do research because “we couldn’t offer anything” to patients with devastating genetic diseases like Rett syndrome and spinocerebellar ataxia. “We didn’t know what was causing these illnesses,” she says.
Today, scientists know the genetic changes responsible for hundreds of childhood diseases and are beginning to develop treatments for some, including Timothy syndrome.
“It’s a dream come true for me,” says Zoghbi….
News Source : www.npr.org
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