A team of Chinese scientists used gene** to correct for a mutation that caused mice to exhibit autistic behaviors such as ADHD, repetitive self-grooming, and abnormal social interactions. Once the mutation is repaired, the animal's behavior returns to normal.
The experiment, described in an article published Nov. 27 in the journal Nature Neuroscience, is the first successful attempt to use genome editing to reverse autistic behavior in an animal model of autism spectrum disorder (ASD). Autism spectrum disorder refers to a variety of disorders characterized by challenges in social skills, repetitive behaviors, and poor communication. These behavioral difficulties can range from barely noticeable to extremely debilitating. One in 36 children in the United States has autism spectrum disorder.
Autism is thought to be caused by a combination of environmental and genetic factors. But while scientists have struggled to convincingly hint at specific environmental influences, they have identified a number of genes that, when mutated, greatly increase the risk of developing autism. One of these genes is called MEF2C. It is directly involved in skeletal muscle growth and vascularization and may play a role in building the cerebral cortex. Mef2c mutations can cause severe ASD in humans. These people are often unable to speak, may grind their teeth incessantly, and may also have epilepsy.
In their experiments, the researchers genetically engineered a series of mice with mutant MEF2C genes. These mice exhibited significant autistic behaviors compared to the unchanged mice. They then used a type of genome editing called base editing to correct the mutation. Lo and behold, rats are starting to behave like their peers.
Genome editing has been synonymous with CRISPR-Cas9 for years. Basic editing is a recent development, dating back to 2016. While CRISPR-Cas9 is essentially a chainsaw that chops off a portion of the DNA strand, base editing is more like a scalpel, targeting individual nucleotides (A, T, C, G) on the strand. CRISPR can make large-scale changes, but sometimes it misfires and cleaves unexpected parts of the DNA. Although base editing is much more accurate, it can only make minor changes to the genome.
In the current experiment, only a minor change is required. Base editing corrected autistic behavior in animals with no significant adverse effects. Another key achievement of the study was to allow editors to cross the blood-brain barrier, a notorious obstacle when it comes to neurological disorders. Scientists guided their precious payload through the barrier by hooking them up to adeno-associated viruses. These basic, tiny viruses are often overlooked by the immune system and can integrate into the host's genome without causing harm.
Taken together, these results establish a framework for the use of genome editing. Correcting genetic mutations in the brain and providing a potential approach for individuals with inherited neurodevelopmental disorders," the researchers wrote.
Other neurological disorders that may also be targeted by base editing include RETT syndrome, fragile X syndrome, Angelman syndrome, and Pitt-Hopkins syndrome.
Overall, I think it's a fascinating observation!Dr. Alysson Muotri, a professor of pediatrics, cellular, and molecular medicine at the University of California, San Diego, told Big Think. Some of Muotri's research has focused on the cellular mechanisms of autism.
He added that the success represents a solid "proof of principle" in the long and tortuous process of ASD**, and warned that replication in humans will take some time.
We are still far from these experiments, both in terms of safety concerns (these enzymes can have potentially harmful off-target) and from actual delivery (the human brain is much larger than a mouse)," he wrote in an email. "But that's how science works, generating data from relevant model systems and moving in the direction of human applications.
Another key caveat of the current experiment is that base editing is only available for small, neat mutations in a single gene. In humans, it is rare to find an example of a mutation that can ultimately be attributed to an individual's disease. This means that basic editing cannot be used as a blanket approach to every form of autism.
Nor should it be. Most people with autism are mentally capable of the same as others, if not higher. As Muotri said in a 2022 presentation, any future gene** is likely to be used only in the individuals most affected by the disease.