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RING 14 NON-PROFIT ASSOCIATION
HELP AND RESEARCH FOR CHILDREN WITH RARE GENETIC DISEASES

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AN INFANTILE RAT MODEL OF EPILEPSY FOR TESTING NOVEL DISEASEMODIFYING DRUGS FOR RING14 SYNDROME

Project Leader
Vezzani Annamaria
Host Institution IRCCS-Mario Negri Institute for Pharmacological Research, Milan (Italy)
Duration 1 year
Start-up date January 2017
Financed amount € 50.000
Status Ongoing
Epilepsy and cognitive disability are serious neurological symptoms in RING chromosome 14 syndrome. 
Typically, epilepsy onset takes place during the first year of life; drug-resistant focal or generalized seizures have a frontotemporal/temporoposterior origin and are frequently associated with episodes of status epilepticus. Epilepsy represents a major complication in almost all cases and does not seem to be related to a structural brain anomaly, it has a stormy onset and is characterized by repetitive and prolonged seizures.
Since at the onset of epilepsy children are usually normally developed from a psychomotor point of view, it is
likely that epileptic activity negatively influences the child psychomotor development, according to the recent
concept of "encephalopathic effect of the epilepsy". Therefore, drugs preventing epilepsy progression after its onset may both preclude the development of pharmacoresistant seizures in children and positively impact on the associated neurological dysfunctions. Notably, febrile infections exacerbate seizures in Ring14 syndrome, thus implying a potential pathogenic role of the immune system. Based on this evidence, we plan to characterize the innate immunity/neuroinflammatory response in the brain of an infant rat model of epileptogenesis induced by de novo status epilepticus, and study whether the severity of the disease is increased by mimicking febrile infections. Notably, this rat model recapitulates key symptomatic features of Ring14 syndrome: rat's age corresponds to the infant/toddler human life, animals develop progressive frontotemporal seizures and cognitive decline in adulthood. Moreover, there is evidence of activation of the brain innate immune response following seizures. 
Our main scope is to characterize this model in-depth for testing if specific anti-inflammatory drugs arrest seizure progression and prevent cognitive deficits and brain atrophy, as we recently showed in adult onset epilepsy.

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