Researchers make ‘exciting first step’ to better understanding development and treatment of autism – BioPharma-Reporter.com

The authors of a paper, published in the journalScience, in an attempt tostudy the function of genes implicated in autism spectrum disorders (ASDs), applied a gene-editing and single-cellsequencing system, Perturb-Seq, to knock out 35 ASD candidate genes in multiple mice embryos.

They described how the Perturb-Seq method they developed can investigate the function of many different genes in many different cell types at once.

Directing the large-scale method to the study of dozens of genes that are associated with ASD, they identified how specific cell types in the developing mouse brain are impacted by mutations.

"The field has been limited by the sheer time and effort that it takes to make one model at a time to test the function of single genes. Now, we have shown the potential of studying gene function in a developing organism in a scalable way, which is an exciting first step to understanding the mechanisms that lead to autism spectrum disorder and other complex psychiatric conditions, and to eventually develop treatments for these devastating conditions," co-senior author Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard.

The method is also broadly applicable to other organs, enabling scientists to better understand a wide range of disease and normal processes, she said.

The study was also led by co-senior authors Aviv Regev, who was a core member of the Broad Institute during the study and is currently executive vice president of Genentech research and early development, and Feng Zhang, a core member of the Broad Institute and an investigator at MIT's McGovern Institute.

"Through genome sequencing efforts, a very large number of genes have been identified that, when mutated, are associated with human diseases. Traditionally, understanding the role of these genes would involve in-depth studies of each gene individually. By developing Perturb-seq for in vivo applications, we can start to screen all of these genes in animal models in a much more efficient manner, enabling us to understand mechanistically how mutations in these genes can lead to disease," said Zhang, who is also the James and Patricia Poitras Professor of Neuroscience at MIT and a professor of brain and cognitive sciences and biological engineering at MIT.

According to the World Health Organization (WHO), the global burden of ASD is continuously growing, with a current prevalence rate of 1 in 160 children.

Reported prevalence rates vary widely from country to country though, according to apaper published in Nature.

Data from the US Centers for Disease Control and Prevention shows that about 1 in 68 children in the US had been identified with some form of ASD, with more than 3 million people affected.A study referenced in the Nature report estimates that the prevalence of ASD in the US in 20142016 was 2.47% among adolescents and children, while in the UK, the annual prevalence rate for children aged 8 years between 2004 and 2010 was 3.8/1000 for boys and 0.8/1000 for girls.

That paper also indicated recent studies showing the pooled ASD prevalence estimate in Asia is 0.36%, including data from nine countries: China, Korea, India, Bangladesh, Lebanon, Iran, Israel, Nepal and Sri Lanka, while the prevalence of ASD in the Middle East region was documented to be 1.4 per 10,000 children in Oman, 4.3 per 10,000 children in Bahrain, and 1/167 in Saudi Arabia.

Moreover, ASD incidence is four to five times greater in males than in females, according to the Nature report.

To investigate gene function at a large scale, the researchers said they combined two powerful genomic technologies. They used CRISPR-Cas9 genome editing to make precise changes, or perturbations, in 35 different genes linked to autism spectrum disorder risk. Then, they analyzed changes in the developing mouse brain using single-cell RNA sequencing, which allowed them to see how gene expression changed in over 40,000 individual cells.

By looking at the level of individual cells, the researchers could compare how the risk genes affected different cell types in the cortex - the part of the brain responsible for complex functions including cognition and sensation. They analyzed networks of risk genes together to find common effects.

"We found that both neurons and glia - the non-neuronal cells in the brain - are directly affected by different sets of these risk genes," said Xin Jin, lead author of the study and a Junior Fellow of the Harvard Society of Fellows. "Genes and molecules don't generate cognition per se - they need to impact specific cell types in the brain to do so. We are interested in understanding how these different cell types can contribute to the disorder."

To get a sense of the model's potential relevance to the disorder in humans, the researchers compared their results to data from post-mortem human brains. In general, they found that in the post-mortem human brains with autism spectrum disorder, some of the key genes with altered expression were also affected in the Perturb-seq data.

"We now have a really rich dataset that allows us to draw insights, and we're still learning a lot about it every day," Jin said. "As we move forward with studying disease mechanisms in more depth, we can focus on the cell types that may be really important."

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Researchers make 'exciting first step' to better understanding development and treatment of autism - BioPharma-Reporter.com