Exploiting whole-brain strategies of gene therapy and novel therapeutic targets in Rett syndrome mouse models

Rett syndrome (RTT) is a severe neurological disorder and second cause of intellectual disabilities in girls. RTT is caused by loss-of-function mutations in the MECP2 gene, which encodes for the methyl-CpG binding protein 2 (MECP2), a global chromatin regulator highly expressed in neurons. Despite all the research efforts, no pharmacological drugs have been obtained yet which significantly ameliorate any key RTT neurological deficits. There is therefore an urgent need to develop innovative therapeutic strategies with direct clinical implication for this disease. RTT is a monogenic disorder caused by mutations in the MeCP2 gene and re-expression of a functional copy of this gene can substantially revert the pathological symptoms even at late stage of the disease in RTT mice. This provides a strong rationale for establishing gene-based therapies to restore the function of the gene to recover or even revert disease manifestations. We have developed new approaches of gene therapy that can restore Mecp2 gene function in RTT mice. Employing a new generation of adeno-associated-viruses (AAVs), we plan to set up interventional strategies to diffuse these therapeutic viruses throughout the brain tissue for a wide re-expression of Mecp2 or other therapeutic genes. However, MECP2 gene duplication in humans is responsible for a serious and clinically distinguished neurodevelopmental disorder. Affected males present with early hypotonia, limb spasticity and severe intellectual disability. Thus, a successful gene therapy for RTT have to deliver the correct MECP2 gene dosage in a very tight range of expression levels. We have devised new viral systems to control Mecp2 gene expression levels to enhance safety levels of these treatments. These approaches have a significant translational potential and offer new therapeutic perspectives for the patients.