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Department Scientists Uncover Drugs That Might Treat ALS

Aug 29, 2022

Department Scientists Uncover Drugs That Might Treat ALS

Working with the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS), Daniel Scoles and Stefan Pulst in the Department of Neurology have performed screens of drug and compound libraries for compounds that prevent the ATXN2 gene from expressing its encoded ATXN2 protein.

The History of ATXN2

Much earlier, in 1996, Pulst’s team had discovered that ATXN2 is mutated in a disorder called spinocerebellar ataxia type 2 (SCA2). Scoles, who had trained and work together with Pulst since 1994, recalls, “Since that time, Pulst had stated that his life’s ambition was to develop a therapeutic targeting ATXN2 for treating SCA2.” Then came a change of events that was even more “lab-shaking”:  a group working at Stanford University discovered that ATXN2 mutations can also cause ALS.

Pulst then joined forces with the Stanford group, and by 2017, they demonstrated that the reduction of ATXN2 expression could dramatically lengthen the lifespan of ALS mice: mice that harbor a human gene known to cause the disease. These events ran simultaneous to work by Scoles and Pulst to develop a completely different therapeutic targeting ATXN2, called antisense oligonucleotide (ASO) therapy. That work was published in the high-impact journal Nature in 2017 in the lead-up to a large NIH grant to Scoles and Pulst that ultimately resulted in the ASO drug BIIB105 that is now being tested in a phase-1 clinical trial for sporadic ALS.

Genetic Engineering to Create a Drug-Screening Strategy

These events also ramped up the need to develop other ways to target ATXN2. Working with Scoles and Pulst, the NCATS team screened nearly a half million compounds in an automated robotic laboratory for compounds that lower ATXN2 expression. The cultured human cell-based screening assay was produced by Scoles, who had used methods of genetic engineering to position the gene that produces light in a firefly—called luciferase—immediately downstream of the regulatory DNA sequence that controls ATXN2. As Dr. Scoles says, “Compounds that turn out the light are ones that likely inhibit ATXN2."

Compounds That Inhibit ATXN2

Compounds discovered in the study included cardiac glycosides that are already used in patients with cardiovascular disorders and HSP90 inhibitors that are being developed in many laboratories across the globe for cancer therapies. Using one HSP90 inhibitor, the team was able to demonstrate that abnormal molecular phenotypes in the central nervous system of SCA2 mice that express the mutant human ATXN2 gene could be normalized when treated with the drug by an intraperitoneal injection. Numerous other compounds that are highly efficacious against ATXN2 with otherwise unknown functions were also discovered. The study was published last month in the Journal of Biological Chemistry.

Strategy for Drug Screening: Compounds Inhibiting ATXN2 Extinguish Light from the Firefly Gene

ALS Infographic