Exacerbation of a Subset of Behavioral Phenotypes by Early Treatment with AAV FOXG1 Gene Replacement Therapy in a Mouse Model of FOXG1 Syndrome

ABSTRACT FOXG1 syndrome is a severe neurodevelopmental disorder characterized by microcephaly, profound intellectual disability with communication deficits including lack of speech, impaired social interaction, increased anxiety, hyperkinetic/dyskinetic movements, seizures and abnormal sleep patterns. Mutations in a single allele of the FOXG1 gene cause disease, likely due to loss-of-function. However, current therapies do not target this root cause of FOXG1 syndrome and have little to modest therapeutic benefit on only a small subset of symptoms. Recently, we reported the beneficial effects of adeno-associated virus (AAV) human FOXG1 gene replacement therapy administered by intracerebroventricular (ICV) injection at postnatal day 6 (P6) on several behavioral deficits that are relevant to key features of human FOXG1 syndrome, in male FOXG1 mice that were engineered with a highly prevalent, patient-specific Q84P mutation. Here, we report the behavioral effects of AAV human FOXG1 gene replacement therapy administered by ICV injection in female as well as male mice and at an earlier age - postnatal day 2 (P2). Although the earlier studies had suggested that AAV FOXG1 gene replacement therapy is a promising approach for the treatment of a subset of functional deficits in human FOXG1 syndrome with no toxicity observations, our current study shows that certain motor behaviors can be negatively impacted or exacerbated by P2 treatment with AAV FOXG1 gene replacement therapy, in female but not male FOXG1 mice. Given these results, the risk-benefit balance of AAV FOXG1 gene replacement therapy in patients with FOXG1 syndrome should be carefully considered, especially in female patients.