New targeted base-editing tool corrects genetic brain disorder in mice

Researchers have found that a new base-editing gene therapy can help treat a rare neurodevelopmental disorder called Snijders Blok–Campeau syndrome caused by mutations in the CHD3 gene. A specialized gene-editing tool, the TadA-embedded adenine base editor (TeABE), was delivered via a harmless modified virus to correct a CHD3 gene mutation in a mouse model.

The editor precisely converted a mutant A–T base pair back to the normal G–C sequence and restored normal CHD3 protein levels, reversing the behavioral and cognitive issues in the mouse caused by the mutation. The findings are published in Nature.

Taming the troublesome gene

The CHD3 gene contains instructions for making a protein that controls gene activity by remodeling chromatin—a complex of DNA and proteins. Using energy from ATP hydrolysis, this protein changes chromatin structure to regulate gene transcription and control how easily DNA can be accessed.

The gene also plays a crucial role in the development of the cerebral cortex. When it is deficient or mutated, neurons may fail to grow properly or migrate to the correct locations during brain development.

One disorder linked to CHD3 is SNIBCPS, which follows an autosomal-dominant pattern of inheritance, where a genetic trait or disorder can be passed down from just one parent to their child. First described in 2018 and with 10 cases recorded since, this disorder has been associated with intellectual disability, speech delays, motor difficulties, and autism spectrum–related behaviors.

While many studies have narrowed down its cause to single-nucleotide variants—changes in a single DNA letter—in CHD3, others have also documented complete deletion and duplication of the CHD3 gene.

There are currently no targeted treatments for SNIBCPS, largely because the specific regions and mechanisms driving the disease are not yet fully understood. At the same time, another fundamental question has remained unanswered: if a harmful mutation in the brain were corrected after birth, could the damage be undone?

With this new study, researchers finally have an answer.

Targeting the right letter

To investigate the disease, the team engineered humanized mice carrying the exact same CHD3 mutation found in people with SNIBCPS. They then examined whether these mice developed learning and behavioral issues similar to those seen in humans.

The model revealed that a recurrent CHD3 variant, p.R1025W, speeds up the breakdown of the CHD3 protein, leading to SNIBCPS-like symptoms in the mice.

For this study, instead of using the well-known CRISPR gene-editing tool, the team designed a base editor (TeABE). Unlike CRISPR, which cuts both strands of DNA, TeABE changes a single letter in the genetic code, making the edit more precise. They used a harmless modified virus—a dual-AAV viral vector system—that is very good at reaching brain cells to deliver the editor.

After the editor ran its course, the researchers noticed that CHD3 protein levels had returned to normal. They also saw that the treated mice were learning better, were being more social, and had much better physical coordination and strength than the untreated ones.

The team also tested this new treatment on macaques’ brains; many nerve cells successfully received the genetic material carried by the viruses.

The researchers are hopeful that, with further study, base editing can move closer to clinical use as a potential treatment for disorders of the central nervous system.

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