ALS is a neurodegenerative disease which affects motor neurons and the neuronal links between our brain and our muscles. Over the course of the disease these nerve links die, and the patient becomes paralyzed, with the majority dying within 2 to 5 years of diagnosis. Around 20% of the familial ALS cases arise from dominant mutations in the Sod1 gene. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits, since they are not even able to slow down the progression of this condition. Now, scientists have taken a significant step forward in the search to find effective new drug candidates for the treatment of this motor neurone disease. Researchers from the Universities of Liverpool (UK) and Nagoya (Japan) have shown that a Selenium-based drug-molecule called ebselen and a number of other novel compounds can change many of the toxic characteristics of a protein, superoxide dismutase (SOD1), which causes some cases of genetic ALS. Indeed, aggregation of mutant SOD1 protein in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease.
The stabilization of the original SOD structure is seen as a key strategy to avoid aggregation. The team have developed a number of ebselen-based compounds with improvements in SOD1 stabilization and in vitro therapeutic effects with significantly better potency than edaravone, which scientists think should work as an antioxidant. Ebselen contains one atom of selenium and it shows some antioxidant enzyme-like activities. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1, a mutant which causes the most severe disease. They were also able to show clear disease onset delay of ebselen in a transgenic ALS model mouse, holding encouraging promise for potential therapeutic compounds.The fact that this new generation of organo-selenium compounds have better in vitro neuroprotective activity than edaravone holds a significance promise for the potential of this class of compounds as an alternative therapeutic agent for ALS treatment. The study is published in the journal EBioMedicine and was supported by a grant from the ALS Association.
According to another recently released results from a clinical trial run by investigators at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) and Amylyx Pharmaceuticals, Inc., an experimental drug combo slows down ALS progression. In 2015, Amylyx along with the scientists’ team developed the CENTAUR Trial. The findings, reported in the New England Journal of Medicine, offer hope that a treatment may one day be available for patients with ALS. Called AMX0035, the oral medication is a combination of two drugs, sodium phenylbutyrate and taurursodiol. The first targets the epigenome mechanism in the cell nucleus, while the second suppresses a protein misfold stress-related mechanism, protecting nervous system against nerve cell death. In the CENTAUR trial, 137 participants with ALS were randomized in a two-toone ratio to receive AMX0035 or placebo. Over six months, participants who were treated with AMX0035 had better functional outcomes than those treated with placebo, as measured by the ALSFRS-R, a questionnaire that evaluates several activities of daily living.
The participants treated with AMX0035 demonstrated a significant slowing of ALS disease progression as measured by the ALSFRS-R. An Open Label Extension trial, in which all patients in the study have been offered AMX0035, is ongoing to assess the medication’s long-term impact.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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