Flunarizine rescues reduced lifespan in CLN3 triple knock‐out Caenorhabditis elegans model of batten disease. Issue 2 (20th October 2016)

• Record Type: Journal Article
• Authors: Kwon, Young Joon; Falk, Marni J.; Bennett, Michael J.
• Is Part Of: Journal of inherited metabolic disease. Volume 40:Issue 2(2017)
• Page Start: 291
• Page End: 296
• Publication Date: 2016-10-20
• Subjects: Metabolism, Inborn errors of -- Periodicals; Metabolism -- Disorders -- Periodicals; 616.39042
• DOI: 10.1007/s10545-016-9986-1
• Languages: English
• ISSNs: 0141-8955

Abstract

Abstract: CLN3 disease (Spielmeyer‐Vogt‐Sjogren‐Batten disease, previously known as classic juvenile neuronal ceroid lipofuscinosis, NCL) is a pediatric‐onset progressive neurodegenerative disease characterized by progressive vision loss, seizures, loss of cognitive and motor function, and early death. While no precise biochemical mechanism or therapies are known, the pathogenesis of CLN3 disease involves intracellular calcium accumulation that may trigger apoptosis. Our prior work in in vitro cell models of CLN3 deficiency suggested that FDA‐approved calcium channel antagonists may have therapeutic value. To further evaluate the potential efficacy of this approach in an otherwise untreatable disorder, we sought to compare the therapeutic effects and underlying mechanisms in an animal model of CLN3 disease. Here, we used the well‐characterized XT7 complete cln‐3 knockout strain of C. elegans to evaluate the therapeutic efficacy of calcium channel antagonist therapy in a living animal model of Batten disease. Therapeutic effects of five calcium channel antagonists were evaluated on XT7 animal lifespan and in vivo mitochondrial physiology. Remarkably, maximal therapeutic efficacy in this model animal was observed with 1 μM flunarizine, the identical concentration previously identified in cell‐based neuronal models of CLN3 disease. Specifically, flunarizine rescued the short lifespan of XT7 worms and prevented their pathophysiologic mitochondrial accumulation. These results confirm the treatment efficacy and dosing of flunarizine in cln‐3 disease in a translational model organism. Clinical treatment trials in CLN3 human patients are now needed to test the dosing regimen and efficacy of flunarizine in individuals suffering with this otherwise untreatable and ultimately lethal neurologic disease.