Gene remedy for uncommon type of autism might deal with one other | Spectrum
Zodiac Signs: Astrocytes from people with Pitt-Hopkins syndrome (center) show high levels of a green marker that is normally only seen in immature cells. After gene therapy (right) the cells show more of a mature cell marker, in purple, similar to control astrocytes (left)
Andrea (Julieth) Sierra Delgado
Increased expression of the gene, which is defective in Rett syndrome, decreases repetitive behavior in a mouse model of another autism-related disorder called Pitt-Hopkins syndrome, a new unpublished study shows.
The researchers presented the results virtually at the Society for Neuroscience’s annual meeting in 2021.
Pitt-Hopkins syndrome results from mutations in a large gene called TCF4. Because the gene is nearly 443,000 letters of DNA, it’s difficult to deliver as gene therapy, says Cassandra Dennys, a researcher at Kathrin Meyer’s lab at Nationwide Children’s Hospital in Columbus, Ohio who presented the work.
In 2018, Dennys colleagues learned of several people with TCF4 mutations who had been mistakenly diagnosed with Rett syndrome. Everyone had Pitt-Hopkins syndrome, but low blood levels of the protein encoded by MECP2, the gene mutated in Rett, Dennys says.
Therefore, the researchers decided to investigate whether MECP2 is altered in cells from humans with Pitt-Hopkins, a first step in testing a gene therapy that increases the expression of MECP2.
“Working closely with patients is very important to us,” says Dennys. “The stories they share and the insights into how their diseases manifest actually help us design research and identify potential therapeutic strategies.”
Deformed cells:
The researchers created immature neural progenitor cells from the skin cells of three people with Pitt-Hopkins syndrome, each with a different TCF4 mutation: a change in a single letter called a missense mutation; a mutation that shortens the TCF4 protein known as truncation; and a deletion of part of the gene.
The progenitor cells derived from all three people had low levels of MECP2 expression, the researchers found.
The team then persuaded the cells to grow into neurons and astrocytes, star-shaped brain cells that physically and functionally support neurons.
The progenitor cells derived from the person with the deletion struggled to differentiate into astrocytes, the researchers found. And the resulting astrocytes were unusual in shape and retained a protein that is normally only seen in immature cells.
“The shape of the cell was something we’ve never seen before,” says Dennys. “You expect a very clear-looking shape, and they weren’t there.”
Neurons that interacted with the poorly differentiated astrocytes struggled to survive, the researchers found. Neurons cultured with astrocytes obtained from the person with the missense mutation did not have this problem, but had an unusual shape, suggesting that the type of mutation affected the type and severity of the results.
“That was one of the most interesting findings,” says Dennys. “The mutation had a very unique effect on the neurons and the differentiation potential of the cells.”
After treating the cells with gene therapy that increases the expression of MECP2, the deficits disappeared, the researchers found.
The team then injected mice lacking a copy of TCF4 with the same gene therapy. After treatment, the mice buried fewer marbles – a sign of reduced repetitive behavior – and showed fewer signs of anxiety and hyperactivity than before.
Dennys says she and her colleagues next want to study cells with other TCF4 mutations to see who could benefit from MECP2 gene therapy.
Read more reports from the Society for Neuroscience’s 2021 Annual Virtual Meeting.
