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May 28

Preliminary clinical trial results for SOD1 ALS look promising

New work from Packard investigator Tim Miller shows encouraging results of an early clinical trial of a new drug to treat ALS caused by mutations in SOD1.

Work presented at the American Academy of Neurology annual meeting in May by Packard scientist Tim Miller, a neurologist at Washington University in St. Louis, shared encouraging results of an early clinical trial of a new drug to treat ALS caused by mutations in SOD1. Tofersen is an antisense oligonucleotide (ASO) that lowers SOD1 levels in the cell and, hopefully, may slow ALS progression. The Phase I/Phase II trial showed that the drug was well-tolerated and lowered SOD1 levels throughout the central nervous system.

“This trial represents a real paradigm change for ALS—turning off an ALS causative gene.  Packard Center clinicians and basic research community are exceptionally excited about this new approach to ALS – reflecting the great convergence of collaborative lab science that came for Packard researchers making its way to our patients.” Jeffrey Rothstein MD, PhD, Director of the Packard Center.

Scientists first linked mutations in SOD1 to ALS in 1993, the first time researchers had been able to show that a specific gene contributed to the disease. Work in the intervening decades by Packard scientists and other investigators around the world showed that the normal job of SOD1 was to protect the cell by converting harmful metabolic waste into water and other non-toxic chemicals. SOD1 mutations, however, didn’t lead to ALS by interfering in this process. Instead, ALS-linked mutations cause the SOD1 protein to misfold, thereby changing its shape. The altered shape of mutant SOD1 makes it ‘sticky,’ causing the mutant protein to clump together in large aggregates. Although scientists don’t know whether these aggregates are toxic because they clog up the cell’s recycling system, because they trap other proteins that help maintain normal cellular processes, or some other reason, animal studies showed that blocking or reducing the formation of SOD1 aggregates could slow disease onset and progression.

One way to lower the amount of SOD1 protein in the cell is to interrupt the process by which the SOD1 gene is transcribed into messenger RNA and then translated into protein. ASOs are a short sequence of 20 nucleotides that are the mirror image of a specific sequence of RNA. When the ASO binds to its target sequence, the cellular machinery can no longer translate the messenger RNA into protein. Over time, cell degrades and recycles existing SOD1 protein and the levels fall. Tests of ASOs in animal models and in induced pluripotent stem cells from patients with SOD1 ALS showed that these ASOs, custom designed by Ionis Pharmaceuticals and Biogen, successfully reduced SOD1 protein levels and slowed disease progression.

In January 2016, Biogen initiated a Phase I/Phase II trials of the SOD1 ASO, known as tofersen, in humans. A total of five doses of the ASO were administered directly into the cerebrospinal fluid over 85 days. The researchers tested a range of doses to determine toxicity and pharmacokinetics at each dose, as well as determine how well tofersen reduced SOD1 levels in the nervous system.

“Overall, the drug was very well-tolerated, and we’re pleased with the pharmacokinetics,” Miller says.

Very few patients reported adverse events, nearly all of which were related to the mode of delivery (lumbar puncture) rather than the drug itself. Preliminary efficacy results, which Miller stresses are extremely limited due to the low number of participants in these initial trials, also appeared promising, as individuals treated with the highest dose of tofersen showed a slower disease progression compared to controls with aggressive forms of SOD1 ALS.

Miller says the results leave him “very optimistic” about an ongoing Phase III trial testing the efficacy of tofersen (to find out more about this study, including eligibility requirements, see the listing at

“We’re excited and we’re also cautious,” Miller says.

Although these trials are targeted towards SOD1 ALS, other early-stage ASO trials for ALS caused by C9orf72 mutations are also underway. As well, Miller notes that this work may allow scientists to match clinical data to biomarkers of disease, allowing them to better predict treatment response and disease progression.