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▎WuXi AppTec content team editor
Recently, scientists at the University of Florida have brought new therapeutic hope to patients with amyotrophic lateral sclerosis (ALS) and dementia, and their study, published in the Proceedings of the National Academy of Sciences, introduced a potential drug molecule that can clear the RNA fragments
that cause the disease.
For ALS patients, the neurons that control their muscles are gradually destroyed, eventually leading to muscle atrophy and death
.
Current studies believe that the gene mutation of C9 open reading frame 72 (C9orf72) is important related to the occurrence of the disease, and this mutation is also believed to lead to the occurrence of frontotemporal dementia, and the temporal cortex of patients will rapidly decrease, resulting in changes
in behavior and language.
The C9orf72 mutation is made up of 6-base "GGGGCC" repeated multiple times, and when the RNA corresponding to this mutated gene is present, it produces harmful proteins and kills nerve cells
.
This highly characteristic gene fragment also led the research team to look for compounds that can block it, and once a molecule can bind to the C9orf72 mutant RNA fragment, then the toxic protein cannot be produced, thereby protecting nerve cells
.
In a sample bank of more than 10,000 potential drug molecules, the team initially identified 69 molecules
that could inhibit the C9orf72 mutant RNA.
Source: 123RF Based on the size and structure of these compounds
, they ruled out candidates who could not enter the blood-brain barrier, because this is a prerequisite for
drugs to help nerve cells.
Of all the remaining molecules, one stands out for its potency, structural simplicity, and what they call compound 1
.
In their tests, compound 1 selectively binds strongly to the C9orf72 mutant RNA, allowing the toxic fragments to be continuously degraded, thereby reducing the production
of toxic proteins.
▲ One of the test samples found in the study that selectively targets ALS-related disease-causing mutations (Image source: Reference [2])
is skin tissue donated by ALS patients, and the research team treated it to return it to the stem cell state, and then artificially let it develop towards neurons.
If the right amount of compound 1 is given at this time, the nascent neurons significantly reduce ALS-related biomarkers
.
This was also confirmed in mice with the C9orf72 mutation, and after two weeks of compound 1 treatment, model mice experienced decreased blood levels of ALS-related markers and healthier behavior
.
This also shows that this molecule is sufficient in animals to function
through the blood-brain barrier.
"We show for the first time that we can make molecules that clear toxic gene products and can deliver them inside the brain," said Professor Matthew Disney, which could lead to new universal approaches
for other neurological disorders.
References: [1] Jessica A.
Bush et al, A blood–brain penetrant RNA-targeted small molecule triggers elimination of r(G 4 C 2 ) exp in c9ALS/FTD via the nuclear RNA exosome, Proceedings of the National Academy of Sciences (2022).
DOI: 10.
1073/pnas.
2210532119[2] Scientists develop RNA-targeting strategy to repair genetic cause of ALS and dementia.
Retrieved November 24, 2022 from https://medicalxpress.
com/news/2022-11-scientists-rna-targeting-strategy-genetic-als.
html
