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

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.”

3 comments

  1. Dave Reckonin says:

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

    The cruel teasing of pALS continues unrelentingly.

  2. Dave Reckonin says:

    “….You have to not only show that a molecule works, but that it is safe,”

    Yeah,,,and your point is?
    Other than ‘Phase 1,2 and 3’stuff ie same old same old ?

  3. This is my favorite kind of research!

    When I worked at the machine shop, I used to run a massive line of really twitchy chemical tanks. Strong acids and bases, dyes, electrochemical tanks (running 2000 amps through a sulfuric solution to build an anodize layer on aluminum parts).

    Whenever I’d get a new person helping me or if there was a new problem I’d never seen before (literally happened almost every day and I have to say I truly enjoyed learning something new every single day) it was hard to get the new guys not to address the symptoms.

    “The pH was way up in tanks 7, 8 and 9 so I adjusted it down with acetic.”

    “Did you do anything about why the pH went up?”

    “What? No, I just adjusted the pH back to normal. Do we need to dump the tanks and start over?”

    “Nah, just wait till the end of the day and add fungicide, adjust the pH again and it should be okay.”

    Almost everyone would try to dump the tank or keep adjusting pH until the tank died and the color changed. Criminy! Fix the problem, don’t treat the symptoms.

    While the new owner was spending tens of thousands of dollars on filters to sift out the sooty-smut that would get on dyed parts, I was trying to figure out where the smut was coming from. For some reason that never occurred to him.

    I worked it out and we ended up with a HUGE board of filters taking up space in our line, that we never used.

    In short (too late) I LOVE that someone’s looking for the cause of ALS so they can address THAT.

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