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The role of mTOR inhibitors in the treatment of autistic symptoms in symptomatic infantile spasms

State/Province Full: 
New York
United States

Infantile spasms are the characteristic seizures of infantile epileptic encephalopathies that often lead to cognitive impairment and pose a high risk for the development of autism spectrum disorders. The current therapies for infantile spasms are not always effective and do not always improve long term outcomes. Using a rat model of infantile spasms, the research team has collected preliminary evidence of an early overactivation of the mTOR pathway in cortical regions during the period of spasms and that normalization of mTOR activity with pulse high dose rapamycin (mTOR inhibitor) stops spasms early and has disease modifying effects as it improves cognitive outcomes. This study aims to determine in the multiple hit model of infantile spasms: (a) the optimal protocol for pulse administration of TORC1 vs. dual TORC1/TORC2 inhibitors that succeed in stopping spasms and improving long term cognitive and behavioral outcomes, including autistic-like symptoms; (b) whether disease modification by mTOR inhibitors is via normalization of the late impairment in GABAA receptor signaling pathway; (c) if combined pulse administration of an mTOR inhibitor with vigabatrin, a GABA-enhancing drug, is superior to either monotherapy in treating spasms, seizures and associated cognitive and autistic-like symptoms. The study uses a combination of stereotactic surgeries, video and video-EEG monitoring, neurodevelopmental and behavioral tests, and histology. It is anticipated that this study will clarify some of the molecular mechanisms underlying the disease modifying effects of mTOR inhibitors in the infantile spasms syndrome. Furthermore, it has the potential to provide the basis for the optimization of novel pulse disease modifying therapies for infantile spasms and associated dyscognitive and autistic symptomatology, with an improved tolerability profile compared to chronic mTOR inhibitor administration.