Two approaches to drug discovery in SODI-mediated ALS

Harvard University, Cambridge, Massachusetts, United States
Journal of Biomolecular Screening (Impact Factor: 2.42). 11/2006; 11(7):729-35. DOI: 10.1177/1087057106290937
Source: PubMed


Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% of these cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). To date, 105 different mutations spanning all 5 exons have been identified in the SOD1 gene. Mutant SOD1-associated ALS is caused by a toxic gain of function of the mutated protein. Therefore, regardless of the specific mechanism whereby mutant SOD1 initiates motor neuron death, the authors hypothesize that measures that decrease levels of mutant SOD1 protein should ameliorate the phenotype in transgenic mice and potentially in patients with SOD1-mediated disease. They have designed 2 cell-based screening assays to identify small, brain-permeant molecules that inactivate expression of the SOD1 gene or increase the degradation of the SOD1 protein. Here they describe the development and optimization of these assays and the results of high-throughput screening using a variety of compound libraries, including a total of more than 116,000 compounds. The majority of the hit compounds identified that down-regulated SOD1 were shown to be toxic in a cell-based viability assay or were nonselective transcription inhibitors, but work is continuing on a number of nonspecific inhibitors of SOD1 expression. Ultimately, the authors believe that these 2 cell-based assays will provide powerful strategies to identify novel therapies for the treatment of inherited SOD1-associated forms of ALS.

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Available from: Aleksey Kazantsev, Oct 06, 2014
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    • "Stem cell-derived neurons are becoming increasingly important in biological research and in devising therapeutic strategies for neurodegenerative disorders, i.e. as replacements for degenerating cells in the central nervous system (CNS) (Gao et al., 2005; Suzuki et al., 2007) and for high-throughput drug screens (Broom et al., 2006; Rubin, 2008). Several groups have generated motor neurons from human embryonic stem cell (hESC) lines (Li et al., 2005; Roy et al., 2005). "
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    ABSTRACT: Human embryonic stem cell (hESC)-derived neurons have the potential to model neurodegenerative disorders. Here, we demonstrate the expression of a mutant gene, superoxide dismutase 1(SOD1), linked to familial amyotrophic lateral sclerosis (ALS) in hESC-derived motor neurons. Green fluorescent protein (GFP) expression under the control of the HB9 enhancer was used to identify SOD1-transfected motor neurons that express human wild-type SOD1 or one of three different mutants (G93A, A4V and I113T) of SOD1. Neurons transfected with mutant SOD1 exhibited reduced cell survival and shortened axonal processes as compared with control-transfected cells, which could survive for 3 weeks or more. The results indicate that hESC-derived cell populations can be directed to express disease-relevant genes and to display characteristics of the disease-specific cell type. These genetically manipulated hESC-derived motor neurons can facilitate and advance the study of disease-specific cellular pathways, and serve as a model system to test new therapeutic approaches.
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    ABSTRACT: The aim of this review is to analyze how our knowledge on the etiology, pathology, and treatment of amyotrophic lateral sclerosis (ALS) has profited from the application of biotechnology tools for the identification of disease markers, the development of animal disease models, and the design of innovative therapeutics. In humans, ALS-specific clinical, genetic or protein biomarkers, or panels of biomarkers stemming from genomics and proteomics analyses can be critical for early diagnosis, monitoring of disease progression, drug validation in clinical trials, and identification of therapeutic targets for subsequent drug development. At the same time, animal models representing a number of human superoxide dismutase 1 mutations, intermediate-filament disorganization or axonal-transport defects have been invaluable in unraveling aspects of the pathophysiology of the disease; in each case, these only represent a small proportion of all ALS patients. Preclinical and clinical trials, although at present heavily concentrating on pharmacological approaches, are embracing the emerging alternative strategies of stem-cell and gene therapy. In combination with a further subcategorization of patients and the development of corresponding model systems for functional analyses, they will significantly influence the already changing face of ALS therapy.
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    ABSTRACT: The pathomechanism of sporadic amyotropic lateral sclerosis is not clearly understood, although a proportion of familial amyotropic lateral sclerosis is caused by superoxide dismutase 1 mutations. Theories based on studies of human post-mortem tissue, research on animal models and in vitro work have been proposed for the pathogenesis of amyotropic lateral sclerosis, but the pathogenesis is not the same between sporadic and familial amyotropic lateral sclerosis. Drug candidates were tested using superoxide dismutase 1 mutant mice. Although the candidates were shown to be effective in mice, clinical trials in humans have failed to identify any truly effective pharmacotherapies in sporadic amyotropic lateral sclerosis, with only riluzole providing a modest improvement in survival. Ongoing or planned trials are exploring the value of antiglutamatergic drugs, antioxidants, neurotrophic factors, anti-inflammatory drugs and anti-aggregation drugs. A combination of drugs acting on different mechanisms is needed for effective therapy. Moreover, gene expression profiling and genome-wide association studies, together with inhibitory RNA techniques, are helpful for developing new pharmacotherapeutic strategies including gene therapy. It is also likely that the recently advanced generation of induced pluripotent stem cells will lead to the development of cell therapy for amyotropic lateral sclerosis. In addition to finding effective therapies, research is also needed in order to detect early disease markers since pharmacotherapy is most beneficial when given early in the course of sporadic amyotropic lateral sclerosis.
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