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For the past 15 years, the field of amyotrophic lateral sclerosis (ALS) pathophysiology and drug development has largely been dominated by understanding the biology surrounding mutations in superoxide dismutase; the first gene mutation identified in familial ALS. In spite of a large amount of research surrounding the pathobiology of this mutation in animal models and in vitro, no successful human therapy has resulted from the many positive preclinical observations and clinical experiments based on mutant superoxide dismutase 1 (SOD1). The identification of two new familial ALS mutations in the past 2 years has potentially dramatically changed that. The identification of the TAR DNA-binding protein (TDP-43) in ubiquitinated protein aggregates found in many patients with sporadic ALS (but not familial SOD1-mediated ALS) or the most common form of frontotemporal dementia called frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) has raised the possibility that this protein may be either a byproduct or an initiator of sporadic ALS (Lagier-Tourenne et al, 2010). The importance of this purely pathological observation was solidified and intensified when dominant mutations of TDP-43 were found in multiple ALS families and may account for up to 3% of familial ALS cases (Lagier-Tourenne et al, 2010). Perhaps equally significant has been the observation that almost all sporadic ALS post-mortem specimens have TDP-43 aggregates present in neurons and glia. Subsequently mutations in the RNA-metabolizing protein FUS were also found in a small subset of familial ALS patients. Thus, a new mechanism of familial ALS pathophysiology, aberrant RNA metabolism, suggested in sporadic ALS a decade earlier (Lin et al, 1998), appears to be an important ALS initiator. Importantly for the investigation of motor neuron disease, animal models using TDP-43 mutations have been developed, which afford a new model for the study of potential ALS-related drug therapies (Wegorzewska et al, 2009).
ALS largely remains a clinical diagnosis based on the presence of upper and lower motor neuron signs that can be observed on physical examination and supported by electrophysiological studies and exclusion of other etiologies using serological and imaging studies. Current efforts are underway with both large consortia and individual groups to identify biomarkers from tissue or fluids that can establish the diagnosis early in the course of disease as well as an assessment of disease progression, identification of ALS subtypes, prediction of disease prognosis, and assessment of the therapeutic efficacy of drug candidates.
Recent advances in the identification of specific genes, which can cause ALS, have fueled the speculation that ALS may be a disease amenable to gene silencing technologies. For the most common ALS disease related gene (SOD1), both RNAi and antisense technologies have been used in transgenic mutant SOD1 animal models of ALS to show effective reduction of the SOD1 protein (Miller et al, 2005). A phase 1 safety trial using the CSF delivery of antisense oligonucleotides targeting SOD1 is now underway in patients with SOD1-mediated ALS (www.clinicaltrials.gov).
Perhaps the most important breakthrough in stem cell biology and its applicability to human diseases has been the ability to reprogram somatic cells into induced pluripotent stem cells (iPSC) using forced expression of the transcription factors Klf-4, Sox-2, Oct-4, and c-Myc, first in rodent, and then from human skin fibroblasts (Yu et al, 2007). Current efforts are underway from different investigators to create iPSC-derived neural stem cells from ALS patients. These iPSCs can subsequently be differentiated into multiple nervous system subtypes to aid in the understanding of cell-specific contributions to the development of ALS, screening for potential neuroprotective and neuroregenerating compounds, and potentially for their therapeutic potential in cell transplantation. The ability of specific CNS cells, such as astroglia, to alter ALS outcomes has been recently shown preclinically (Lepore, 2008). In parallel, the first commercial attempt to develop cellular-based therapies for ALS has entered into clinical trial. The proper cell for therapy is controversial and efforts, to date, appear to lack rigorous preclinical/drug discovery science. However, the first challenge in this invasive-type therapy is the development of appropriate surgical methods to deliver cells intraspinally to patients—and excellent efforts toward that goal appear underway in a recent phase 1 trial (www.clincialtrials.gov).
Dr Rothstein received compensation for serving as a scientific advisor to Cytokinetics, Pysadon Pharmaceuticals, Repligen, for clinical and/or preclinical drug discovery programs. He also serves as a grant reviewer for Muscular Dystrophy Association, National Institute of Health, Robert Packard Center for ALS Research at Johns Hopkins. Dr Maragakis serves as a grant reviewer for the US Department of Defense. He is a nonpaid scientific consultant to Q Therapeutics Inc.