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CLN3 iPSC manuscript-STM.pdf (1.84 MB)

Small Molecules that Rescue Multiple Phenotypic Aberrations in an iPSC-Derived Neuron Model of CLN3 Disease

submitted on 02.01.2020, 03:05 and posted on 02.01.2020, 16:51 by Nihar Kinarivala, Ahmed Morsy, Ronak Patel, Angelica Carmona, Md. Sanaullah Sajib, Snehal Raut, Constantinos M. Mikelis, Abraham Al-Ahmad, Paul C. Trippier

The neuronal ceroid lipofuscinoses (NCLs) commonly referred to as Batten disease are a family of rare lysosomal storage disorders (LSDs). The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with the current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier (BBB) and adds to the few available iPSC-derived neuron models of the disease. Upon differentiation, hallmarks of CLN3 disease were displayed including lipofuscin and subunit C of mitochondrial ATP synthase accumulation, mitochondrial dysfunction and aberrant lysosomal pH. Small molecules were identified that cleared subunit C accumulation by the mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction.


UT Southwestern Center for Translational Medicine (UL1/KL2/TL1)

National Center for Advancing Translational Sciences

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Texas Tech University Health Sciences Center

University of Nebraska Medical Center


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University of Nebraska Medical Center



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Declaration of Conflict of Interest

N.K. and P.C.T are inventors on a patent application (PCT Int. App. WO 2019014547) submitted by Texas Tech University that covers the composition of matter of the compounds described herein. P.C.T. serves as an advisor to Circumvent Pharmaceuticals Inc

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