Identification and Characterization of Cholest-4-en-3-one, Oxime (TRO19622), a Novel Drug Candidate for Amyotrophic Lateral Sclerosis

Washington University in St. Louis, San Luis, Missouri, United States
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 09/2007; 322(2):709-20. DOI: 10.1124/jpet.107.123000
Source: PubMed


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.

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    • "Using gentle FACS conditions , we were able to isolate more than 60.000 pure motor neurons from a single 24-well iPSc culture on a routine basis, which should allow refined transcriptomic and proteomic profiling of patientderived motor neurons. The FACS-isolated human motor neurons survive at a similar rate as rodent motor neurons, which have been instrumental in demonstrating the neuroprotective properties of Riluzole (Estevez et al., 1995), Olesoxime (Bordet et al., 2007) and other pharmacological compounds now in clinical use. Scalable cultures of FACSisolated human iPSc-derived motor neurons thus hold promise for improved drug testing and screening in human motor neuron diseases. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease. Human motor neurons generated from induced pluripotent stem cells (iPSc) offer new perspectives for disease modeling and drug testing in ALS. In standard iPSc-derived cultures however, the two major phenotypic alterations of ALS - degeneration of motor neuron cell bodies and axons - are often obscured by cell body clustering, extensive axon criss-crossing and presence of unwanted cell types. Here, we succeeded to isolate 100% pure and standardized human motor neurons by a novel FACS double selection based on a p75(NTR) surface epitope and an HB9:RFP lentivirus reporter. The p75(NTR)/HB9::RFP motor neurons survive and grow well without forming clusters or entangled axons, are electrically excitable, contain ALS-relevant motor neuron subtypes and form functional connections with co-cultured myotubes. Importantly, they undergo rapid and massive cell death and axon degeneration in response to mutant SOD1 astrocytes. These data demonstrate the potential of FACS-isolated human iPSc-derived motor neurons for improved disease modeling and drug testing in ALS and related motor neuron diseases. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; 82. DOI:10.1016/j.nbd.2015.06.011 · 5.08 Impact Factor
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    • "Because of the wide occurrence of mitochondrial dysfunction not only in mouse models with different causal mutations but also in sporadic patients, drugs that target these abnormalities are of therapeutic interest. Dexpramipexole, olesoxime and creatine, three compounds modulating mitochondrial function, showed promising results in preclinical studies, but failed in clinical trials (Bordet et al., 2007; Cudkowicz et al., 2013; Martin, 2010; Pastula et al., 2012; Shefner et al., 2004; Sunyach et al., 2012). Currently, new strategies to improve mitochondrial function in ALS mice are explored. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. It is a neurodegenerative disorder with high genetic and phenotypic variability. In most patients, the cause of the disease is unknown. Until now, no treatment strategy has been discovered with the exception of riluzole which has a moderate effect on the disease process. While developing a new causal therapy targeting a specific disease-causing gene can have a huge effect on the disease process, only a limited number of ALS patients will benefit from such a therapy. Alternatively, pathogenic processes that are common in ALS patients with different etiology can also be targeted. The effect of such a modifying treatment will be smaller, but the target population will be larger as more ALS patients could benefit. In this review, we summarize the evidence for the involvement of different biological processes in the pathogenesis of ALS and will discuss how strategies influencing these processes can be translated into new therapeutic approaches. In order to further improve this translational step, there is an urgent need for a better understanding of the underlying mechanism(s), for new ALS animal models and for rigorous protocols to perform preclinical studies.
    Experimental Neurology 12/2014; 262. DOI:10.1016/j.expneurol.2014.07.001 · 4.70 Impact Factor
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    • "Apomorphine-S was identified through an in-house screening cascade of CNS-penetrant Nrf2 activators (Barber et al., 2009), and has been observed to delay the onset of ALS symptoms in transgenic G93A SOD1 mice (Mead et al., 2013). Olesoxime has been demonstrated to prolong motor neuron survival via modulation of the mitochondrial permeability transition pore and was recently evaluated in a phase 3 trial in human ALS (Bordet et al., 2007). Dose-response curves were conducted to establish an optimal drug concentration. "
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    ABSTRACT: Mutations in the superoxide dismutase gene (SOD1) cause familial amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) in humans. ALS is a relentlessly progressive neurodegenerative disease and to date there are no neuroprotective therapies with significant impact on the disease course. Current over-expressing mutant SOD1 transgenic murine models have so far been ineffective in the identification of new therapies beneficial in the human disease. As the human and the zebrafish (Danio rerio) SOD1 protein share 76% homology, TILLING (Targeting Induced Local Lesions IN Genomes) was carried out in collaboration with the Sanger Institute in order to identify mutations in the zebrafish sod1 gene. A T70I mutant zebrafish line was characterised using oxidative stress assays, neuromuscular junction analysis and motor function studies. The T70I sod1 zebrafish model offers the advantage over current murine models, of expressing the mutant Sod1 protein at a physiological level, akin to human ALS patients. The T70I sod1 zebrafish demonstrate key features of ALS; an early NMJ phenotype; a susceptibility to oxidative stress, and an adult onset motor phenotype. We have demonstrated that the susceptibility of T70I sod1 embryos to oxidative stress can be used in a drug screening assay, to identify compounds that merit further investigation as potential therapies for ALS.
    Disease Models and Mechanisms 10/2013; 7(1). DOI:10.1242/dmm.012013 · 4.97 Impact Factor
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