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Endocrinologist Joan C. Han, MD, and researchers at several universities and the National Institutes of Health (NIH) explored whether genetic tools could be used to repair the corpus callosum, the structure connecting the two hemispheres of the brain. When development of the corpus callosum is abnormal, results include disorders such as schizophrenia, intellectual disability and autism spectrum disorder.

Since genetic mutations may contribute to abnormal development of the corpus callosum, the researchers focused on a gene associated with intellectual disability (C11orf46) to see if mutations in this gene were also associated with changes in the corpus callosum.

Examined by MRI, the corpus callosum was significantly smaller in patients with only one normal copy of C11orf46 than in those with two normal copies.

The researchers blocked C11orf46 expression in developing mice to determine if it would change the developing corpus callosum. Following knockdown of C11orf46, axons, which enable communication between neurons and form the corpus callosum, failed to make connections between the two hemispheres of the brain. These changes also reduced the size of the corpus callosum in mice, similar to the MRI findings in humans.

Loss of C11orf46 increased the expression of Sema6a, a gene that regulates axon development. When Han and colleagues used epigenetic editing (a tool that adjusts gene expression without mutating DNA) to lower Sema6a expression to normal levels, the ability of axons to form the corpus callosum and connect the two hemispheres was restored, despite the absence of C11orf46. These findings indicate the possibility for early intervention in neurodevelopmental disorders.

Peter CJ, Saito A, Hasegawa Y, et al. In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene. Nat Commun. 2019;10(1):4112. Published 2019 Sep 11. doi:10.1038/s41467-019-12013-y