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PNAS: breaks through the blood-brain barrier, targets pathogenic RNA, treats ALS and dementia

 Last Update: 2023-01-05
 Source: Internet
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Written byWang Cong
EditorWang Duoyu TypesettingWater Writing

Amyotrophic lateral sclerosis (ALS), also known as ALS, is one of the five terminal diseases recognized by the World Health Organization (WHO), which is a chronic, progressive degenerative disease involving upper/lower motor neurons and their innervated trunk, limbs and head and facial muscles, in which patients gradually lose neurons that control muscles, resulting in muscle atrophy.
Eventually death
.

C9orf72 gene mutation is the main cause of hereditary frostbite, abnormal amplification of the hexanucleotide repeat (GGGGCC, G4C2) in the C9orf72 gene, repeated 65 times to tens of thousands of times, this abnormal amplification, not only affects the normal expression of the C9orf72 gene, but also produces one A neurotoxic protein called Dipeptide Repat Proteins (DRP).

This abnormal amplification mutation of the C9orf72 gene, in addition to causing ALS, is also an important causative factor of frontotemporal dementia, accounting for about 25% of frontotemporal dementia, which causes atrophy of the frontal and temporal lobes of the brain, causing changes in personality, behavior and language, and eventually leading to death
.

On November 21, 2022, researchers from the Scripps Institute published a report in PNAS entitled: A blood–brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome Research papers
.

The study found a small molecule drug candidate capable of breaking through the blood-brain barrier, selectively eliminating the G4C2 abnormally amplified RNA fragment of the C9orf72 gene that causes ALS and frontotemporal dementia, and restoring the health
of ALS neurons and mouse models.

Professor Matthew Disney, corresponding author of the paper, said that this compound eliminates disease-causing RNA (intron retention caused by abnormal amplification of G4C2) by binding and utilizing the natural processes of cells.
Allow these released intronic RNAs to be cleaned up as waste through exosomes
.
It is conceivable that this method could also be applied to other neurological diseases
that are currently untreatable due to the effects of toxic RNA.

First author Jessica Bush (left) and corresponding author Matthew Disney (right)
first screened from 11,000 drug-like molecules at the Scripps Research Institute.
First, 69 compounds that inhibit the translation of toxic C9orf72 mutations were identified.

Then, the research team further refined these compounds, proposed those compounds that could not pass through the blood-brain barrier according to factors such as molecular size and structure, and further screened 16 candidate compounds, of which one compound (compound 1) had the most potential and was used for further study
.

The team tested skin cell samples donated by ALS patients from the Neurodegenerative Research Laboratory at Johns Hopkins University School of Medicine, who induced skin cells into stem cells that then differentiated into neurons
.

Testing of skin cell-induced neurons derived from 4 ALS patients, compound 1 resulted in a dose-dependent reduction of ALS markers without off-target effects
.

The team also tested the compound on mouse models of ALS that carried mutations in the C9orf72 gene, which showed typical ALS behaviors and hematologic markers
.
Two weeks after treatment, the mouse model of ALS had significantly fewer disease markers and improved health
.

Professor Matthew Disney said the evidence so far showed that this approach represented a significant advance
in RNA drug discovery.
This study is the first to show that you can develop molecules that cross the blood-brain barrier and eliminate toxic gene products, and this was demonstrated in ALS
.
This can be a universal treatment
for neurological disorders including frostbite, frontotemporal dementia, Huntington's disease, muscular dystrophy, etc.

Link to the paper: style="letter-spacing: normal;color: rgb(136, 136, 136);font-size: 12px;" _mstmutation="1" _istranslated="1">
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