An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis.
Shannon L MacauleyAndrew M S WongCharles ShyngDavid P AugnerJoshua T DearbornYewande PearseMarie S RobertsStephen C FowlerJonathan D CooperD Martin WattersonMark S SandsPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2014)
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.
Keyphrases
- gene therapy
- blood brain barrier
- cerebral ischemia
- traumatic brain injury
- small molecule
- lipopolysaccharide induced
- lps induced
- poor prognosis
- high fat diet induced
- neuropathic pain
- cell proliferation
- inflammatory response
- signaling pathway
- temporal lobe epilepsy
- squamous cell carcinoma
- cognitive impairment
- stem cells
- brain injury
- long non coding rna
- spinal cord injury
- metabolic syndrome
- machine learning
- gene expression
- mesenchymal stem cells
- wild type
- replacement therapy
- helicobacter pylori
- data analysis
- helicobacter pylori infection
- bone marrow
- artificial intelligence
- resting state
- rectal cancer
- oxide nanoparticles