Modeling ALS
How C9orf72 mouse models of ALS could accelerate therapeutic development
The discovery of a mutation in the chromosome 9 open reading frame 72 (C9orf72) region as the most common genetic cause of amyotrophic lateral sclerosis (ALS) over four years ago has led to new mechanistic understanding of the disease and even new therapeutic candidates, but progress has been limited by a lack of mouse models that capture the pathology. Two separate groups have developed mice that express the human gene with the mutation and recapitulated the biochemical characteristics of the disease - but not the cognitive ones. However, that might not be a show-stopper in a field that is moving towards emphasizing genetic over behavioral models for drug development.
Most preclinical research in ALS has been performed in patient-derived cells, including induced pluripotent stem (iPS) cell-derived neurons containing the mutation, and in zebrafish. Although some mouse models of ALS do exist, notably the mutant superoxide dismutase 1 (SOD1) mouse model, they don't capture the unique features of the C9orf72-mutant form of the disease, which is characterized by an increased number of GGGGCC hexanucleotide repeats within the C9orf72 region. ...