Terapia a base di precursori neurali/cellule staminali per la sindrome di Rett/Neural precursor/stem cell-based therapy for Rett syndrome

MECP2 mutations cause Rett syndrome (RTT), the first cause of severe intellectual disability in girls. Neural Precursor Cell (NPC) transplantation was proved safe and efficacious in many neurological disorders, including autism. Willing to respond to the unmet need of a cure for RTT, we investigated the therapeutic potential of adult NPCs in Mecp2 deficient mice, modelling RTT. Although the prime mechanism of action of NPCs is the replacement of damaged cells, transplanted cells also exert their benefits through a bystander mechanism. Indeed, by sensing the pathological environment, they promote immunomodulation, neuroprotection and brain plasticity through the secretion of several molecules. Moreover, transplanted NPCs adapt their fate and functions to the specific pathological context and can engage in a rich talk with resident cells. Our data demonstrate that NPC transplantation prolongs the lifespan of Mecp2 null mice, restoring memory and motor functions. After administration, NPCs localize along the meninges in the caudal zone of the brain by maintaining an immature phenotype, suggesting the involvement of a paracrine effect. Therefore, using a transwell-based co-culture system, we confirm the paracrine action of NPCs to promote synaptic rescues in Mecp2 deficient neurons. Also, by exploring the beneficial effects of their secreted factors, we prove the NPC ability to adapt their phenotype depending on the pathological context. In order to identify the molecular mechanisms behind NPC efficacy, an RNA-seq study disclosed the possible involvement of the Interferon (IFN)γ pathway. Coherently, the IFNγ recombinant molecule was effective in reverting motor and cognitive impairments in Mecp2 null animals and in improving synaptic alterations of RTT neurons. Together, our data provide the "proof of concept" of a NPC-based therapy for RTT and indicate the involvement of IFNγ, which might be proposed as a novel therapeutic strategy.