New Small Molecule Targets Root Cause of ALS and Frontotemporal Dementia, Study Reports

Researchers have developed a new small molecule that targets the most common genetic defect behind amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, a study reports.

These findings suggest that therapies directed at the underlying cause of ALS and frontotemporal dementia may be achievable in the near future.

The study, “The Hairpin Form of r(G4C2)^expin c9ALS/FTD is Repeat-associated non-ATG Translated and a Target for Bioactive Small Molecules,” was published in the journal Cell Chemical Biology.

The most common genetic cause of ALS and frontotemporal dementia is an expansion of a short sequence of DNA, composed by the nucleotides (the building blocks of DNA) GGGGCC on chromosome 9.

This leads to the production of repeat-containing RNAs — the chemical cousins of DNA — which accumulate inside cells and lead to toxic events. These transcripts exist as two differently arranged structures, either as hairpin or G-quadruplex structures.

A second toxic mechanism linked to these transcripts is that cells may use them as templates to produce sequence-repetitive proteins, called C9RAN, which accumulate in nerve cells and disrupt their normal metabolism, causing them to die.

In ALS, the death of motor neurons — those bridging the central nervous system to muscle cells — cause muscle shrinkage, or atrophy, and weakness, leading to paralysis. In frontotemporal dementia, the toxic accumulation of the peptides is the underlying cause of death of neurons in two specific regions of the brain, called the frontal and temporal lobes, which control behavior and personality.

Researchers at The Scripps Research Institute in Florida and their colleagues have now developed a small molecule they simply call “4,” which in vitro (lab) studies have shown is capable of targeting the hairpin-arranged RNAs.

While “often the G-quadruplex is presumed to be the therapeutically relevant structure,” the researchers found evidence that the hairpin is also a contributor to the disease, supporting its relevance as a target for therapies, they said.

This is because by targeting the hairpin structures, the researchers were able to disrupt the production of the C9RAN proteins, which didn’t happen with small molecules targeting the G-quadruplex forms.

These in vitro studies show that a small molecule targeting the hairpin structure can inhibit the toxicity linked with GGGGCC repeats, the researchers said.

“There are zero therapies that address the root cause of this disease. Our goal is not to target the symptoms, it is to target the root cause, which is that RNA,” Matthew Disney, PhD, the study’s first author said in a press release. “Hopefully, this will be an accelerant not only for us but for all people in the field working toward a treatment for ALS.”

However, developing a new potential therapy is a long process and the one for small molecule 4 has just begun.

“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,” Disney said. “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.”