Neurodevelopmental disorders (ND) are chronic psychiatric conditions with different etiologies, but most share a strong genetic component, defective brain development, and cognitive impairment. Currently, treatment options are very limited, and early educational intervention is the cornerstone for the management of cognitive impairment in most ND, indicating the positive effect of early actions during brain development. Among ND, Down syndrome (DS) is caused by the presence of an extra chromosome 21, and it represents the leading cause of genetically-defined intellectual disability. Different pharmacological treatments targeting one of the many pathways downstream of the triplicated genes have been shown to rescue cognitive impairment in DS animal models. Nevertheless, most of these preclinical studies have been performed postnatally and often in adults, possibly because of concerns of unwanted drug side effects that may have long-lasting noxious sequelae on a developing brain at embryonic stages. On the other hand, viral (but also non-viral) gene therapy approaches in animal models of ND have been mostly neglected because of technical and ethical issues, when considered in the light of future translational applications. Yet, DS is mostly diagnosed prenatally, when many of its brain developmental abnormalities originate. Here, we investigated whether early in life manipulation by gene-therapy and pharmacological approaches on known, but also newly discovered converging gene-networks (relevant for the human condition) in neurons of DS mice may recover brain development, cognitive deficits, but also other comorbidities later in life. This approach avoided the involvement of genetic editing of germline cells and all related ethical issues. In parallel, we improved (viral-free) technological approaches for genetic manipulations in utero to minimize technical issues in the view of potential future translational applications.
Our investigation highlighted common pathways dysregulated in people with DS and mouse models, indicating a prevalent role for inflammation, early developmental processes such as axonogenesis, and possibly new targets. Early-in-life gene therapy/pharmacological interventions had long-lasting effects in the absence of any drug and led to rescue of behavioral phenotypes and molecular signatures that therapeutic interventions during adulthood could not rescue. In this context, although viral-free strategies lead to significant results in animal models (mostly in utero electroporation, which has low translational value), their potential applications in patients still seem to be far away in the future, due to low efficiency of sonoporation.
