RT Journal Article SR Electronic T1 An Anti-Neuroinflammatory That Targets Dysregulated Glia Enhances the Efficacy of CNS-Directed Gene Therapy in Murine Infantile Neuronal Ceroid Lipofuscinosis JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 13077 OP 13082 DO 10.1523/JNEUROSCI.2518-14.2014 VO 34 IS 39 A1 Shannon L. Macauley A1 Andrew M.S. Wong A1 Charles Shyng A1 David P. Augner A1 Joshua T. Dearborn A1 Yewande Pearse A1 Marie S. Roberts A1 Stephen C. Fowler A1 Jonathan D. Cooper A1 D. Martin Watterson A1 Mark S. Sands YR 2014 UL http://www.jneurosci.org/content/34/39/13077.abstract AB Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). Studies in Ppt1−/− mice demonstrate that glial activation is central to the pathogenesis of INCL. Astrocyte activation precedes neuronal loss, while cytokine upregulation associated with microglial reactivity occurs before and concurrent with neurodegeneration. Therefore, we hypothesized that cytokine cascades associated with neuroinflammation are important therapeutic targets for the treatment of INCL. MW01–2-151SRM (MW151) is a blood–brain barrier penetrant, small-molecule anti-neuroinflammatory that attenuates glial cytokine upregulation in models of neuroinflammation such as traumatic brain injury, Alzheimer's disease, and kainic acid toxicity. Thus, we used MW151, alone and in combination with CNS-directed, AAV-mediated gene therapy, as a possible treatment for INCL. MW151 alone decreased seizure susceptibility. When combined with AAV-mediated gene therapy, treated INCL mice had increased life spans, improved motor performance, and eradication of seizures. Combination-treated INCL mice also had decreased brain atrophy, astrocytosis, and microglial activation, as well as intermediary effects on cytokine upregulation. These data suggest that MW151 can attenuate seizure susceptibility but is most effective when used in conjunction with a therapy that targets the primary genetic defect.