Abstracts

Rationale: Infantile spasms (IS) are age-specific epileptic seizures typically observed in infantile epileptic syndromes such as West syndrome. IS manifest as clusters of flexion or extension spasms and have poor prognosis. Better therapies are needed. Early spasm cessation may have some disease modifying effect in patients of unknown IS etiologies whereas structural etiologies render IS more refractory to current treatments: adrenocorticotropic hormone (ACTH) or vigabatrin. We previously reported that a pulse protocol of rapamycin, an mTOR inhibitor, suppressed spasms and partially improved learning in the multiple-hit rat model of IS due to structural etiology. Therefore, to identify mTOR inhibitors with better therapeutic potential for IS, we tested the efficacy of a dual TORC1/TORC2 inhibitor, Torin1, in suppressing spasms in the multiple-hit rat model of IS.Methods: On postnatal day 3 (PN3) Sprague-Dawley male rats received doxorubicin (DOX) (right intracerebroventricular) and lipopolysaccharide (LPS) (right intraparietal) infusions under isoflurane anesthesia to induce the model, followed by intraperitoneal p-chlorophenylalanine on PN5. Daily monitoring of weights, surface righting time, open field activity, and negative geotaxis were recorded from PN3-PN5. On PN4, after the onset of spasms, a single dose of Torin1 (1, 5, or 10 mg/kg intraperitoneally [i.p.]) or vehicle was administered to assess drug efficacy on spasms and intermittent video-monitoring was done on PN4 and PN5. A randomized, blinded, dose and time response study design was followed. Sample size was 11-14 rats per dose group.Results: All doses of Torin1 administered as a single injection after the onset of spasms, acutely reduced both the raw and normalized frequencies of spasms in the multiple-hit model, for up to 5 hours dose-dependently. Dose-related differences were observed in the timing of the effects of Torin1 on spasms. Torin1 was well tolerated and had no effect on neurodevelopmental reflexes. Only the high dose was associated with slower weight gain rate during the treatment period.Conclusions: The outcomes of this study further support the role of mTOR signaling in the pathogenesis and treatment of IS in the multiple-hit model. There was a dose-dependent reduction of spasms following a single injection of Torin1 in the multiple-hit model of refractory IS within the first 5 hours post injection. Torin1 is therefore a promising candidate drug for further evaluation for the treatment of IS. This project was funded by CURE (Infantile Spasms Initiative), NINDS (NS078333), Department of Defense and the Heffer Family and Segal Family Foundations and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/ Dan Levitz families.