Human tridimensional neuronal cultures for phenotypic drug screening in inherited peripheral neuropathies.

Human tridimensional neuronal cultures for phenotypic drug screening in inherited peripheral neuropathies. Clin Pharmacol Ther. 2019 Nov 12;: Authors: Maciel R, Correa R, Taniguchi JB, Araujo IP, Saporta MA Abstract Length-dependent axonal degeneration is the pathologic hallmark of several neurodegenerative disorders, including inherited peripheral neuropathies (Charcot-Marie-Tooth disease, CMT). 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 two-dimensional configuration of neuronal cultures, which limits visualization and orientation of axons. To overcome these limitations, we cultured iPSC-derived spinal motor neurons as three-dimensional 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 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. PMID: 31715019 [PubMed - as supplied by publisher]
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Tags: Clin Pharmacol Ther Source Type: research