Summary: A new compound eliminates pathogenic segments of RNA associated with ALS and dementia, and restores healthy neurons in mouse models.
Source: University of Florida
Scientists at the University of Florida (UF) Scripps Biomedical Research have developed a potential drug for a major cause of ALS and dementia that works by removing disease-causing RNA segments. The compound restored the health of neurons in the lab and saved mice with disease.
The potential drug is described this week in the scientific journal Proceedings of the National Academy of Sciences. It’s designed to be taken as a pill or injection, said lead inventor Professor Matthew Disney, Ph.D., chairman of the UF Scripps Department of Chemistry.
Importantly, the experiments showed that the compound is small enough to cross the blood-brain barrier, a hurdle that other approaches have failed to overcome, he said.
Amyotrophic lateral sclerosis, or ALS, progressively destroys neurons that control muscles, leading to further muscle loss and eventually death. The mutation, one of the main causes of inherited ALS, is called
“C9 open reading frame 72” or C9orf72. This mutation also leads to a form of frontotemporal dementia, a brain disease that causes the frontal and temporal lobes of the brain to shrink, leading to changes in personality, behavior and speech, ultimately leading to death.
The C9orf72 mutation presents an enlarged six-letter repeat of the genetic code, GGGGCC, on chromosome 9, which can be duplicated between 65 and tens of thousands of times.
When this mutated segment of RNA is present, it results in the production of toxic proteins that sicken and eventually kill affected neurons. The compound developed by Disney’s lab targets the RNA carrying these genetic instructions, preventing toxic proteins from assembling in cells.
“The compound works by binding to and using natural cellular processes to remove this pathogenic RNA by alerting the cell’s breakdown machinery to dispose of it as waste,” Disney said.
This approach could potentially work for other incurable neurological diseases in which toxic RNA plays a role, he added.
The first author of the paper is Jessica Bush, a graduate student from the Skaggs Graduate School of Chemical and Biological Sciences at UF Scripps, who works in the Disney lab. Other co-authors include Leonard Petrucelli, Ph.D., of the Mayo Clinic in Jacksonville, and Raphael Benhamou, a former Disney Lab postdoctoral researcher now on the faculty of the Hebrew University of Jerusalem.
“This was identified from a large screen of compounds in Scripps Research’s Calibr library, which includes 11,000 drug-like molecules,” Bush said.
From this initial screen, they identified 69 compounds that inhibited translation of the toxic C9 mutation. They then refined the compounds by eliminating those that could not cross the blood-brain barrier based on size, weight, structure and other factors. This resulted in 16 candidate compounds, one of which was selected for further refinement based on its potency and structural simplicity.
“A battery of tests in neurons derived from ALS patients and in vivo models showed that Compound 1 binds selectively and avidly to toxic RNA, causing it to be degraded by the body’s natural processes,” Bush said. .
Patients being treated for ALS at the Johns Hopkins University School of Medicine Neurodegenerative Research Laboratory have donated skin samples for research. These skin cells were genetically transformed into stem cells, after which the Disney team treated the cells for several months to grow into neurons.
“Four cells from different patients were used for the evaluation, all of which showed a dose-dependent reduction in known ALS markers while having no off-target effects,” Bush said.
They also tested the compound in mice bred to have the C9orf72 mutation and show behaviors and blood markers typical of ALS. The mice were treated daily for two weeks, after which the mice showed significantly reduced disease markers and improved health.
The next steps will be to further study the compound’s effects on cellular health and rodent models of C9 ALS, Disney said. The evidence so far shows that this approach represents a notable advance in the field of RNA-based drug discovery, he said.
“We are showing for the first time that you can make brain-penetrating molecules that remove toxic gene products,” Disney said. “The fact that we have highlighted this in ALS shows that this may be a general approach for other neurological diseases, including Huntington’s disease, forms of muscular dystrophy and others.”
About this genetics and ALS research news
Author: Press office
Source: University of Florida
Contact: Press Office – University of Florida
Image: Image is in public domain
Original research: Free access.
“A small molecule RNA-targeted entry into the blood and brain triggers the elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome” by Jessica A. Bush et al. PNAS
RNA-targeted small molecule entering blood and brain triggers elimination of r(G 4 C 2 ) exp in c9ALS/FTD via nuclear RNA exosome
A repeated hexanucleotide expansion in intron 1 of the C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD.
RNA transcribed from the expansion, r(G4VS2)expcauses various pathologies including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci.
Here we describe a small molecule that potently and selectively interacts with r(G4VS2)exp and attenuates pathological pathologies in c9ALS patient-derived induced pluripotent stem cell (iPSC) differentiated spinal neurons and in two c9ALS/FTD mouse models.
These studies reveal a mode of action by which a small molecule decreases intron retention caused by r(G4VS2)exp and allows the released intron to be removed by the nuclear RNA exosome, a multi-subunit degradation complex.
Our results highlight the complexity of the mechanisms available for RNA-binding small molecules to alleviate disease pathologies and establish a pipeline for the design of brain-penetrating small molecules targeting RNA with novel modes of action. in vivo.
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