Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has now been achieved. Fudan University and Shanghai Jiao Tong University School of Medicine scientists created the cytosine base editor (AeCBE) system to change C·G to T·A base pairs. The Chinese scientists used this system to target a mutation in mice linked to ASD successfully. This work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.
The research article “Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice” was published in Nature Neuroscience.
Developing gene therapy for autism
Rare de novo variants, including single-nucleotide (SNVs) and copy number variants, have been confirmed as important contributors to the pathogenesis of ASD, a highly heritable neurodevelopmental disorder characterized by deficits in social interaction and stereotypic behaviors.
People with ASD and intellectual disabilities were found to have recurrent de novo variants of the myocyte-specific enhancer factor 2C (MEF2C) gene, which is a member of the MEF2 transcription factor family. In particular, mutations in MEF2C have been identified in cohorts with ASD in East Asia, including China and Korea. Children with mutations in MEF2C or microdeletions of the chromosomal segment 5q14.3-q15 that contains MEF2C exhibit characteristics of ASD, lack of speech, intellectual disabilities, and epilepsy.
MEF2C is abundantly expressed in adult mice’s cortex, hippocampus, and amygdala. MEF2C and other members of the MEF2 family have important roles in neuronal differentiation, neural development, and synaptic plasticity. These findings strongly suggest that MEF2C haploinsufficiency affects brain development.
This work identified a de novo SNV in the MEF2C gene—a thymine-to-cytosine conversion resulting in a lysine-to-proline amino acid change—in an individual with ASD. To investigate the functional effects of this mutation, the researchers created mice with this same mutation. They found that male mice with the mutation had reduced protein expression in the brain and exhibited social deficits, hyperactivity, and repetitive behaviors.
To correct this mutation in the brain, the researchers intravenously injected an AAV construct, AAV-PHP.eB, that can cross the blood-brain barrier. The new AeCBE-mediated base editing method was sufficient to increase the levels of Mef2c protein and fix the mice’s social behavior problems and repetitive behaviors brought on by the de novo SNV.
These findings provide a foundation for correcting genetic mutations in the brain through genome editing in vivo and offer potential treatment options for people with genetic neurodevelopmental disorders. Since base editors only edit regions from C to T and A to G, using base-editing systems that target a wider range of regions, such as prime editing, would greatly assist in creating genetic tools to treat genetic disorders.