Targeted RNA to prevent dementia that penetrates the blood-brain barrier

Amyotrophic lateral sclerosis (ALS), also known as ALS, is one of
the five terminal diseases recognized by the World Health Organization (WHO).
It is a chronic, progressive degenerative disease that affects the upper and lower motor neurons and muscles
of the trunk, extremities, head, and face.
Patients gradually lose neurons that control muscles, resulting in muscle atrophy and eventual death
.

Hexanucleotide repeat amplification of GGGGCC (G4C2exp) located in the first intron of chromosome 9 Open Reading Box 72 (C9orf72) is the most common genetic cause
of familial amyotrophic lateral sclerosis (ALS).
Healthy individuals typically retain fewer than 30 G4C2 repeats in the C9orf72 gene, while affected individuals have more than 65 repeats, often in the thousands
.
Toxic RNA from replicate expansion, r(_G4C2)^exp, induces disease pathology by at least two mechanisms: (i) non-canonical translation of extended replicates [repeat-associated non-AUG (RAN) translations], producing toxic dipeptide repeats (DPRs) and (ii) toxic foci consisting of replicate extensions and various RNA-binding proteins (RBPs), RNA isolation and inactivation
.

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

Recently, researchers at the Scripps Institute published a research paper
in PNAS.
This study identified a small molecule drug candidate that can break through the blood-brain barrier and selectively eliminate the G4C2 abnormally amplified RNA fragment of the C9orf72 gene that causes cryomorphic and frontotemporal dementia, restoring the health
of faded neurons and mouse models.

Professor Matthew Disney, corresponding author of the paper, said that the compound can bind and exploit the natural processes of cells, eliminating pathogenic RNAs (abnormal amplification of G4C2 leads to intron retention), so that these released intron RNAs are cleared as waste
products through exosomes.
It is conceivable that this approach could also be used for other neurological disorders
for which there are currently no drugs due to the action of toxic RNA.

The first step in the study was to screen 11,000 drug-like molecules
from the Scripps Institute.
First, the researchers identified 69 compounds that inhibit the translation
of the toxic C9orf72 mutation.
Subsequently, the research team further refined these compounds, proposed compounds that could not pass the blood-brain barrier according to factors such as molecular size and structure, and further screened out 16 candidate compounds
.
One of these compounds (Compound 1) has the most potential and can be used for further research
.

The team tested skin cell samples
donated by frozen patients from the Neurodegenerative Research Laboratory at the Johns Hopkins University School of Medicine.
They induced the skin cells of these patients to become stem cells, which then differentiated into neurons
.
Skin cell-induced neurons were tested in 4 patients with ALS, and compound 1 was found to reduce the dose-dependent nature of ALS markers without off-target effects
.

The team also tested the compound on a frozen mouse model with a mutation in the C9orf72 gene, which showed typical frost-freeze behavior and hematologic markers
.
After 2 weeks of treatment, the disease markers of progressive ALS were significantly reduced and the health status improved
.

Professor Disney said the study was the first to demonstrate that we could develop molecules that cross the blood-brain barrier, eliminating toxic gene products and demonstrated this
in the case of ALS.
This represents a major advance
in RNA drug discovery.
This can become a universal treatment for neurological disorders such as ALS, frontotemporal dementia, Huntington's disease, muscle wasting, etc
.

Bush J A, et al.
A blood–brain penetrant RNA-targeted small molecule triggers elimination of r (G₄C₂)^exp in c9ALS/FTD via the nuclear RNA exosome.
Proceedings of the National Academy of Sciences, 2022, 119(48): e2210532119.