PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice.

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the () gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic variants correlated with overexpression of (), a gene linked to white matter disorders. Postnatal administration of -targeting antisense oligonucleotides (ASOs) in c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.