New Gene Therapy Restores Brain Mechanism Linked To Autism

Scientists have managed to restore an important communication mechanism between neurons using a new gene therapy. In autism models, the treatment improved brain and behavioral changes, bringing new hope for the development of more precise and personalized therapies.

Autism spectrum disorder is a neurodevelopmental condition that affects communication, social interaction, and behavior. Although its causes are quite varied, many studies indicate that alterations in the way neurons communicate play an important role.

One of the main systems involved in this communication uses so-called NMDA receptors, structures present on the surface of neurons that function as "gateways" for chemical signals essential to learning, memory, and the proper development of brain connections. When these receptors function below normal, various cognitive functions can be impaired.

Problems in the activity of these receptors have already been associated not only with autism, but also with schizophrenia and a rare autoimmune disease called NMDA receptor encephalitis. In recent years, researchers have tried to increase the activity of these receptors by raising levels of glycine, a substance that helps the NMDA receptor function correctly.

However, clinical results have been inconsistent. One reason is that the medications used increased glycine in many regions of the brain at the same time, including areas responsible for vital functions, making it difficult to achieve a precise and safe effect.

In this new study, scientists decided to follow a different strategy. Instead of directly increasing glycine throughout the brain, they sought to block a protein called SLC6A20, responsible for transporting this molecule in regions important for cognition, such as the cerebral cortex and hippocampus.

To do this, they used a technology known as antisense oligonucleotides. These small synthetic fragments of genetic material function as a kind of "blocking message": they enter cells and reduce the production of a specific protein, allowing its activity to be modified in a highly targeted way.

This approach has already been used in other genetic diseases and represents one of the most promising areas of precision medicine.

The researchers conducted the experiments using different models. First, they applied the treatment to mice genetically modified to exhibit mutations in the SHANK2 and SHANK3 genes, alterations known to be associated with some forms of autism in humans.

These animals exhibit difficulties in social communication, repetitive behaviors, and alterations in NMDA receptor activity, reproducing some of the characteristics observed in some patients. After receiving treatment, many of these behaviors improved, although the degree of recovery varied depending on the mutation present in each model.

In addition to animal studies, the team also used human brain organoids, small structures produced in the laboratory from stem cells that reproduce part of the development of the cerebral cortex. These "mini-brains" contained the same mutations found in patients with alterations in the SHANK2 or SHANK3 genes.

When the researchers reduced the activity of the SLC6A20 protein in these organoids, they observed a recovery in the functioning of NMDA receptors, suggesting that the strategy may also work in human cells and not just in animal models.

The authors emphasize that this research is still an initial step. The treatment has only been tested in experimental models, and safety studies and clinical trials in humans will still be necessary before any medical application is possible.

Furthermore, autism spectrum disorder is extremely heterogeneous, and probably only some groups of patients with specific alterations in NMDA receptors will be able to benefit from this approach. Even so, the study represents an important advance by demonstrating that it is possible to restore a fundamental brain mechanism using highly targeted gene therapy, opening new perspectives for more personalized treatments in the future.

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Glycine-modulating Slc6a20a-ASO restores NMDA receptor function in SHANK2 and SHANK3-mutant mice and cortical organoids

Junyeop Daniel Roh, Mihyun Bae, Yusang Oh, Yeji Yang, Suho Lee, Woo-Chang Hwang, Esther Yang, Hyeonji Kim, Hyunjee Jang, Hyung-Wook Choi, Hyun Kim, Jin Young Kim, and Eunjoon Kim

Nature Communications. 29 May 2026, DOI: 10.1038/s41467-026-73881-9

Abstract: 

Suppressed NMDA receptor (NMDAR) function contributes to multiple brain disorders, including schizophrenia, autism spectrum disorder (ASD), and NMDAR encephalitis. Previous attempts to restore NMDAR activity by increasing ambient glycine, a critical co-agonist, through GlyT1 inhibition have yielded mixed outcomes, partly due to GlyT1’s extensive expression in essential brainstem regions. Slc6a20a, a glycine transporter widely expressed in cognition-relevant regions such as the cortex and hippocampus, offers a targeted alternative. Here we show that antisense oligonucleotide (ASO)-mediated Slc6a20a inhibition (Slc6a20a-ASO) normalizes ASD-related phenotypes in male Shank2- and Shank3-mutant mice, with model-dependent rescue profiles. Slc6a20a-ASO rescues NMDAR hypofunction and synaptic phospho-proteomic profiles in the prefrontal cortex. Furthermore, ASO targeting human SLC6A20 rescues suppressed NMDAR function in cortical organoids harboring SHANK2 or SHANK3 mutations. These findings underscore the potential and limitations of Slc6a20a/SLC6A20-ASO for treating disorders characterized by NMDAR hypofunction.