Newly discovered ALS mechanism could point the way to novel drugs

One of the major known causes of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding SOD1 that cause the protein to fold in the wrong way, and aggregated SOD1 has been found in the motor neurons of both familial and sporadic ALS patients. Researchers at the Umeå University in Sweden have now discovered how the rogue protein can “transmit” its morbidity to other normal proteins.

Examining misfolded SOD1 is difficult, so the ALS team at Umeå developed an antibody-based method called “binary epitope mapping” to analyze the molecular structure of protein aggregates. Using the new technique, the team found two types of SOD1 clumps that drive ALS.

“One type gave rise to a more aggressive disease progression, which shows that these aggregates are the driving force in the development of ALS,” said Johan Bergh, a doctoral student at Umeå University, in a statement.

Bergh injected the purified human SOD1 clumps grown in mice into lumbar spinal cords of two types of mouse models. The animals soon became terminally ill with ALS. What’s more, “a tem­plated spread of aggregates along the neuraxis was concomitantly observed,” said Bergh in his doctoral thesis (PDF). This suggests that the aggregates act as templates to spread the misfolding, and hence the disease, from neuron to neuron.

Researchers are developing drugs that target the SOD1 protein. One such drug, dubbed BIIB067, which is being developed by Biogen and Ionis, works on the SOD1 gene in mRNA to prevent protein production. In preclinical studies, the drug extended survival in rats and also delayed muscle weakness symptoms in mice. The drug is currently in phase 1/2 clinical testing.

RELATED: PARP inhibitors show promise for treating ALS and other brain disorders

In a recent study published in Nature Communications, a team at the University of Liverpool found that an anti-inflammatory molecule called ebselen could stabilize mutant SOD1.

Other efforts are underway to repurpose drugs for use in ALS. Orion Pharma, for example, just pushed its heart failure drug Simdax (levosimendan) in a phase 3 trial in ALS, despite mixed phase 2 results. New research from the University of Pennsylvania also suggests PARP inhibitors, including cancer drugs Lynparza by AstraZeneca’s Lynparza and Zejula by Tesaro, could prevent a toxic protein called TDP-43 from forming clumps in the brain.

Bergh hopes future drugs will attack the SOD1 aggregates. "Using the new method, we have shown and confirmed through animal models that the development of ALS follows the same principle as for other severe nervous disorders. Protein aggregates function as a template that healthy proteins stick to and cause the disease to spread," he said.