ALS hope at last?

Small-molecule targets may prevent ALS

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JUPITER, Fla.—Florida researchers have homed in on a compound believed to arrest the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and related forms of dementia. Dr. Matthew Disney from The Scripps Research Institute, working in collaboration with Dr. Leonard Petrucelli of the Mayo Clinic in Jacksonville, Fla., believes they have uncovered a novel small-molecule compound that may well translate into a preventative drug candidate.
“There are zero therapies that address the root cause of these diseases. Zero. Our goal is not to target the symptoms, it is to target the root cause, which [we believe] is in the RNA,” explains Disney. “We are assessing its potential to become a drug to treat both diseases. Hopefully, this will be an accelerant not only for us but for all people in the field working toward a treatment for ALS.”
The scientists had been investigating the cellular mechanisms that cause neurodegeneration in diseases characterized by abnormal protein aggregation, such as Alzheimer’s disease, frontotemporal dementia (FTD) and ALS. It is the death of the nerve connectors between muscles and the brain that leads to ALS symptoms of muscle atrophy, weakness, difficulty swallowing and trouble breathing. In frontotemporal dementia, the toxic protein appears to be a cause of neuron death in parts of the brain that control behavior and personality, the frontal and temporal lobes. Disney’s compound, a small molecule he designed, is simply referred to as “4” in the paper. It interferes with production of the toxic C9RAN protein, he notes.
The team found that the causative DNA lies in a non-coding section of the ninth chromosome, where a repeating pattern of letters GGGGCC stimulates the production of a toxic substance, C9RAN. According to Disney, when C9 undergoes RAN translation (RANT), it produces toxic peptides that disrupt normal cell metabolism in ALS and FTD patients, causing neuron death. Thus, developing compounds that can target the repeats and inhibit its RANT would be a useful therapeutic option.
“These and other studies by my lab have shown beyond a shadow of a doubt that RNA is druggable with small molecules. Not just for ALS but other genetically defined diseases, cancers and infectious diseases,” Disney says.
An article published recently in the journal Cell Chemical Biology details the mechanism of the newly understood compound, which hampers the successful creation of the protein known to cause ALS. In working to identify small-molecule drug candidates, the lab recently discovered that inhibition of the enzyme HDAC6 may be an effective strategy to effectively arrest the toxic accumulation of tau protein, which is associated with Alzheimer’s disease and related dementia.
“The findings mean that small molecules that target RNA are a potential therapeutic option for ALS. Our compound works differently than most drugs on the market. Rather than binding with the toxic protein behind the disease, it binds with what’s involved in making the protein, a specific form of RNA folded over like a hairpin,” Disney tells DDNews. “Since RNA molecules manage the expression of genes, intervening at the RNA level goes right to the apparent cause of that form of the disease.”
“We have a long and winding road to make this into a drug. You have to not only show that a molecule works, but that it is safe,” he points out. “Now that we have a target and we know how to bind it, this should accelerate making compounds that could become drugs in a much more streamlined way.”
For Disney and his colleagues, the next steps will be to apply their findings to animal models searching for optimal medicinal chemistry for the best possible therapeutic outcomes. “We have good reason to believe that this can be done,” Disney says. “The question is would potency and selectivity be enough to get to a patient and ‘do no harm.’ We are very optimistic.”

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