title: An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis.
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.
authors.affiliation: Department of Neurology, Department of Internal Medicine, and.
authors.forename: Shannon L
authors.identifier: http://orcid.org/0000-0002-4292-2703
authors.initials: SL
authors.lastname: Macauley
authors.affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom, and.
authors.forename: Andrew M S
authors.initials: AM
authors.lastname: Wong
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Charles
authors.identifier: http://orcid.org/0000-0001-6451-2847
authors.initials: C
authors.lastname: Shyng
authors.affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom, and.
authors.forename: David P
authors.initials: DP
authors.lastname: Augner
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Dearborn
authors.affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom, and.
authors.forename: Yewande
authors.initials: Y
authors.lastname: Pearse
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Marie S
authors.initials: MS
authors.lastname: Roberts
authors.affiliation: Departments of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Fowler
authors.affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom, and.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.affiliation: Department of Internal Medicine, and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, msands@dom.wustl.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000628:therapy*; D011724:Pyridazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use; D012640:Seizures / Q000628:therapy; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C524807:MW01-2-069A-SRM; D011724:Pyridazines; D011743:Pyrimidines; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase
keywords: Batten disease; lysosomal storage disease; neurodegeneration; neuroinflammation; neuronal ceroid lipofuscinosis