An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis

Shannon L. Macauley, Andrew M.S. Wong, Charles Shyng, David P. Augner, Joshua T. Dearborn, Yewande Pearse, Marie S. Roberts, Stephen C. Fowler, Jonathan D. Cooper, Martin M. Watterson, Mark S. Sands

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)13077-13082
Number of pages6
JournalJournal of Neuroscience
Volume34
Issue number39
DOIs
StatePublished - Sep 24 2014

Keywords

  • Batten disease
  • Lysosomal storage disease
  • Neurodegeneration
  • Neuroinflammation
  • Neuronal ceroid lipofuscinosis

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