Researchers in the Wilson Lab study Friedreich ataxia (FA), an inherited neuro- and cardio-degenerative mitochondrial disorder. The lab has made important contributions to the basic understanding of FA, finding in early studies that knocking out the yeast homolog of the FA disease protein, frataxin, causes profound mitochondrial dysfunction; that disease-associated missense mutations are associated with a gradual loss of mitochondrial function; and that human frataxin can substitute for its yeast homolog (Nature Genetics 16: 352). Follow-up studies have confirmed the yeast-model findings in human-derived cells, and in patients, findings that include mitochondrial dysfunction and defects in cellular iron metabolism.
The Wilson Lab constructed the first shRNA-expressing libraries that are completely random at the nucleotide level (U.S. Patent 9163231). The lab uses these libraries in a pooled, unbiased approach to identify and optimize shRNA sequences that confer favorable phenotypes (as shRNAs or as siRNAs) in cell-culture disease models. Using primary FA fibroblasts, the lab used gene-expression and bioinformatic analyses of hit shRNAs to identify conventional chemical-compound therapeutic and drug-target candidates. The lab can now effectively screen 3 million bioactive molecules in a single tissue-culture dish, screening for efficacy and lack of toxicity simultaneously. Screens for additional disorders, including cystic fibrosis and primary mitochondrial disorders, are in progress.
Finally, the lab has experience in more conventional drug development, specifically for FA, having designed and implemented high-throughput screens of >350,000 chemical compounds. The lab has also developed several FA models for secondary testing, including iPSC-derived cardiomyocytes and zebrafish. In addition to testing drugs developed in the lab, the team has used their models to test compounds developed by pharmaceutical companies and other academic investigators.
Identification of p38 MAPK as a novel therapeutic target for Friedreich's ataxia.
Ferroptosis as a novel therapeutic target for Friedreich's ataxia.
An iPS-derived cardiomyocyte model of Friedreich ataxia.
Oleic acid and oleic acid derivatives as a treatment for Friedreich ataxia.
Phenotypic screening for the mitochondrial disorder MELAS using random shRNA selection.