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Human Tridimensional Neuronal Cultures for Phenotypic Drug Screening in Inherited Peripheral Neuropathies.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2020 May; Vol. 107 (5), pp. 1231-1239. Date of Electronic Publication: 2019 Dec 14. - Publication Year :
- 2020
-
Abstract
- Length-dependent axonal degeneration is the pathologic hallmark of several neurodegenerative disorders, including inherited peripheral neuropathies (Charcot-Marie-Tooth (CMT) disease). CMT is currently an untreatable disorder. This is partially due to lack of translational models suitable for drug discovery. In vitro models of CMT have been hindered by the 2D configuration of neuronal cultures, which limits visualization and orientation of axons. To overcome these limitations, we cultured induced pluripotent stem cell (iPSC)-derived spinal motor neurons as 3D spheroids, which grow axons in a centrifugal fashion when plated. Using these iPSC-derived spinal spheroids, we demonstrate neurofilament deposits in motor neuron axons of three patients with CMT2E, caused by mutations in the NEFL gene. This phenotype is partially reversed by two kinase inhibitors. In summary, we developed a human tridimensional in vitro system that models length-dependent axonopathies, recapitulates key pathophysiologic features of CMT2E, and should facilitate the identification of new therapeutic compounds for CMT.<br /> (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Axons
Cell Culture Techniques
Cells, Cultured
Charcot-Marie-Tooth Disease genetics
Drug Discovery methods
Humans
Mutation
Neurofilament Proteins genetics
Peripheral Nervous System Diseases genetics
Phenotype
Charcot-Marie-Tooth Disease physiopathology
Models, Anatomic
Motor Neurons cytology
Peripheral Nervous System Diseases physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 107
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 31715019
- Full Text :
- https://doi.org/10.1002/cpt.1718