Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in the CLN3 gene. JNCL presents between 5-10 years of age, with progressive vision loss, seizures, cognitive and motor decline, and death by late teens-early 20s. There is no treatment for JNCL, which underscores the significance of identifying novel therapeutics to improve lifespan and quality-of-life for children suffering from this deadly disease. Recent work from our laboratory suggests that aberrant glial activation during early JNCL may contribute to neuronal loss. In particular, CLN3?ex7/8 microglia are primed to produce numerous proinflammatory mediators with known neurotoxic effects, whereas wild type (WT) cells are non-responsive. Astrocyte hemichannel (HC) opening is also enhanced in numerous brain regions of CLN3?ex7/8 mice, which allows the non-discriminant passage of molecules from the intra- to extracellular milieus and disruption of physiologic gradients. The combination of early HC opening and aberrant microglial activation in JNCL likely disrupts the brain metabolome, contributing to the pathological chain of events that culminates in neuronal loss. Our hypothesis is that targeting aberrant glial activation with two classes of compounds that affect multiple pathways will significantly delay JNCL progression. The first, INI-0602, is a novel HC inhibitor that reduces glutamate accumulation in CLN3?ex7/8 mice to levels typical of WT animals. The other group includes the second generation phosphodiesterase-4 (PDE4) inhibitors Roflumilast and PDE4 subtype specific inhibitors provided by Pfizer that attenuate proinflammatory mediator production by CLN3?ex7/8 microglia and also increase astrocyte glutamate transporter expression. Importantly, both INI-0602 and PDE4 inhibitors reduce inflammation and neuronal loss in numerous disorders, including AD and HD. This R21 proposal will identify the optimal neuroprotective regimens for INI-0602 and PDE4 inhibitors, by evaluating effects on the brain metabolome, behavior, and neuronal survival in CLN3?ex7/8 mice. We will establish optimal dose-response profiles for each drug, the ideal therapeutic window for intervention, and whether INI-0602 and PDE4 inhibitors display additive effects in a combinational therapy approach. The preclinical assessment of INI-0602 and PDE4 inhibitors as novel therapeutics to delay JNCL progression will be examined in the following specific aims: 1) The hemichannel inhibitor INI-0602 attenuates glutamate accumulation during early JNCL, leading to significant neuronal sparing in thalamocortical structures;2) PDE4 inhibitors reduce neuronal loss in JNCL by attenuating proinflammatory mediator release and glutamate accumulation;and 3) A combinational therapy with INI-0602 and PDE4 inhibitor provides superior efficacy to impede JNCL progression due to distinct mechanisms of drug action. Together, our novel rationale for compound selection, supporting preliminary data for INI-0602 and PDE4 inhibitors as JNCL therapeutics, and existing intellectual property for these compounds in JNCL, form a solid foundation for the preclinical testing outlined in this R21 application.

Public Health Relevance

Juvenile Batten Disease is an autosomal recessive inherited disorder, with symptoms first apparent between the ages of 5-10, beginning with vision loss and progressing to uncontrolled seizures, gradual motor and cognitive decline, and premature death, with a lifespan of late teens to early 20s. Currently, there is no cure for Juvenile Batten Disease therefore, the objective of this preclinical study is to explore the efficacy of two drug classes t significantly delay disease progression. These drugs were selected based on their ability to inhibit multiple abnormal responses in glial cells that may contribute to neuronal loss.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Morris, Jill A
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University of Nebraska Medical Center
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