Largest ever ‘map’ of autism may hold clues for new targeted therapies

Pauline Chan reports on a major milestone in better understanding autism spectrum disorder and how the findings could help develop targeted therapies.

Scientists are getting a step closer to understanding exactly how autism develops in the brain – and what might work to treat it.

Using artificial intelligence and data on tiny brains grown in the lab, researchers have mapped out the ways in which certain genetic mutations that are associated with autism can rewire the brain and lead to the condition. The molecular map, published Thursday in the journal Science, could help inform more targeted therapies for autism.

“You need this insight to ultimately develop drugs, and we’ve generated a map now that is providing essentially the molecular underpinnings of autism and pointing us in a multitude of different directions for ultimate drug discovery,” said study author Dr. Nevan Krogan, professor at the University of California, San Francisco and senior investigator at the non-profit Gladstone Institutes.

“The hope would be at some point you’d be looking back and saying, ‘Ah, this map led to X, Y, and Z, and therefore we have now the first-ever treatment to autism.’ That’s the vision, and I believe that’s going to come to fruition at some point in the future,” Krogan said.

For decades, developing effective treatments for autism has been a scientific puzzle.

Since there are more than 250 genes associated with autism spectrum disorder, finding a treatment that targets the genetic roots of the disorder is equivalent to seeking a single key for hundreds of different locks.

But now, the new study reveals how many of these diverse genetic mutations physically connect and rewire protein interactions in the developing brain, driving the emergence of autism. Proteins are molecules that physically build and help maintain the brain. So instead of needing hundreds of different drugs to target the genes themselves, scientists now have a blueprint to target the protein interactions instead.

“When you have the genes and the mutations, that’s just a list. That’s a parts list,” said Krogan, who also serves as director of the Quantitative Biosciences Institute at UCSF.

“What you need to do is have a wiring diagram of that parts list, and that’s where you need to go to the proteins and understand how the proteins talk to one another, and understand when you put a mutation in a protein, what does it do to the protein-protein interactions?” he said. “So, understanding that will point you down therapeutic roads that you just could not have ever imagined if you were simply just looking at the genes and the mutation.”

Krogan said that his colleagues and he already have three programs currently underway to develop potential new therapies, using insights from the new study.

Building an autism map

To build the autism map, researchers from the University of California, San Francisco systematically mapped out how genetic mutations tied to autism may influence interactions between proteins in the brain. They found more than 1,800 protein-protein interactions tied to autism, among which 87 per cent of those interactions had never been seen before.

The researchers created the map in the presence of the genetic mutations to understand how the proteins were “rewired” and then used an artificial intelligence system called AlphaFold to prioritize key mutations that were then studied in lab-grown brain organoids.

“AI is allowing us to study proteins that we could never have even dreamed of even a couple of years ago, and it’s providing an unprecedented light being shone on autism, the underlying biology behind autism,” Krogan said.

The map is “the largest that has ever been done on autism,” he said. “It’s the largest map of its kind for any neuropsychiatric disorder, but it’s also the largest mutant map that’s ever been generated for any disease area.”

The new study “is really exciting in that it represents the most systematic protein-level view of autism risk we’ve had to date,” Fikri Birey, assistant professor in the Department of Human Genetics at Emory University School of Medicine, who was not involved in the study, wrote in an email.

“In the future, it may be possible to identify drugs that stabilize disrupted protein complexes or block pathological interactions, rather than trying to correct every individual autism-causing mutation,” Birey wrote, adding that the new study findings could help inform the disease-modeling research conducted in his own lab.

‘Watershed moment for autism’

While the new study offers a map of molecular pathways through which autism may develop, it may not be definitive for every person with autism or every type of the disorder – as the study remains most directly relevant to people with profound autism, who account for about 30 per cent of people with autism spectrum disorder.

“So those are ones that, for example, need 24-hour care,” Krogan said.

However, he added that the study’s findings on protein-protein interactions still could help inform other neuropsychiatric conditions too, including schizophrenia, obsessive-compulsive disorder and tic disorders, as well as other diseases including cancer.

Autism experts and advocates alike have applauded the new study, as it may open the door for more research into potential treatments.

“Today’s study shows where different autism genes converge on shared biological pathways, and those shared pathways could ultimately give us therapeutic targets relevant to much larger groups of autistic people, including people without an identified genetic cause. That is nothing short of a huge watershed moment for autism science,” Alison Singer, president of the non-profit Autism Science Foundation, who was not involved in the new study, wrote in an email.

“For families of people with profound autism like mine, this is the kind of scientific advance we have been waiting for and praying for. Many people with profound autism have rare genetic variants and the promise of precision medicine has always been that understanding those variants would eventually allow us to move beyond treating symptoms and behaviours, and begin addressing the underlying biology,” Singer wrote.

“There is still a lot of work ahead and these discoveries today need to be translated into drug candidates and then tested for safety and effectiveness, but the path from genetic discovery to treatment has just become much clearer.”

While the new research is “exciting,” the non-profit Autism Speak’s chief science officer Dr. Andy Shih cautioned that translating the study’s findings into potential therapies would take a significant amount of time.

“Translating these kinds of discoveries into therapies is a long process,” Shih wrote in an email. “This study provides valuable insights into potential targets, but much more research is needed before these findings can lead to clinical applications.”

Autism has become a major focus of the second Trump administration’s Department of Health and Human Services, under which the Interagency Autism Coordinating Committee (IACC) helps develop and update the national strategic plan for autism research. A new draft plan is up for a committee vote on Thursday.

Singer said that she is not convinced that the new draft plan will usher in more research on the biological targets of autism like what was found in the new study. Rather, she said that she has some concerns that the Trump administration may steer attention away from the current science and instead focus on an unproven link between vaccines and autism.

The federal plan for autism research “deemphasizes genetics, neurodevelopment, and brain biology in favour of a broad injury model that is not consistent with the direction of contemporary autism science,” Singer wrote. “Redirecting limited federal research investments away from the strongest biological evidence will slow scientific progress precisely when these types of unprecedented opportunities for therapeutic development are emerging.”

But Shih of Autism Speaks said that he expects the new IACC strategic plan will include more research into the genetic changes linked with autism.

“There is significant interest in understanding developmental trajectories in the new IACC strategic plan,” he wrote. “And I would expect that continued investment in large-scale, data-driven approaches will lead to more studies examining how genetic factors contribute to autism and affect development.”

By Jacqueline Howard, CNN