An iPSC-Derived Neuron Model of CLN3 Disease Facilitates Small Molecule Phenotypic Screening

Nihar Kinarivala, Ahmed Morsy, Ronak Patel, Angelica V. Carmona, Md Sanaullah Sajib, Snehal Raut, Constantinos M. Mikelis, Abraham Al-Ahmad, Paul C. Trippier

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


The neuronal ceroid lipofuscinoses (NCLs) are a family of rare lysosomal storage disorders. 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 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 and establishes the suitability of an iPSC-derived neuron model of the disease to facilitate compound screening. Upon differentiation, hallmarks of CLN3 disease are apparent, including lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and attenuated Bcl-2 expression. The model led to the identification of small molecules that cleared subunit c accumulation by mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)931-947
Number of pages17
JournalACS Pharmacology and Translational Science
Issue number5
StatePublished - Oct 9 2020


  • CLN3 disease
  • apoptosis
  • autophagy
  • blood-brain barrier
  • drug discovery
  • phenotypic screening

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology


Dive into the research topics of 'An iPSC-Derived Neuron Model of CLN3 Disease Facilitates Small Molecule Phenotypic Screening'. Together they form a unique fingerprint.

Cite this