DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE
The aim of the research
Rett Syndrome is a neurological disorder affecting mainly girls, who exhibit normal development for the first 6-18 months of life, but then manifest a gradual loss of motor skills, social withdrawal, and mental retardation.
The cause of this devastating condition is believed to be mutations in a gene called Mecp2. One of the most debilitating symptoms od RTT is represented by severe epilepsy, which is often resistant to common therapies. Using a RTT mouse model it has been demonstrated that neurons are not irreversibly damaged and symptoms might therefore be cured. These studies demonstrate that a better understanding of the pathophysiologic processes leading to RTT might help developing therapeutic strategies. Notably, splicing events occur mainly in the central nervous system and participate in setting threshold of neuronal excitability together with fundamental neuronal processes, from cell-related ones, such as nerve growth and synapse formation to higher cognitive functions, including learning and memory. Although promising, this area is still poorly investigated in the RTT research field. In this framework is placed our research program. We identified a new MeCP2 downstream target whose splicing is markedly altered in RTT mouse models. This target is a protein involved in epigenetic regulation of transcription and its function is fundamental for neuronal maturation and synaptogenesis, and to modulate neuronal excitability, processes impaired in RTT. With our proposal we intend to test the possibility to ameliorate RTT symptoms in particular epilepsy, using short DNA molecules named antisense oligonucleotides that can interfere with the pathological splicing processes.