Scientists at UF Scripps Biomedical Research have developed a potential drug for a leading cause of ALS and dementia that works by eliminating disease-causing segments of RNA. The compound restored neuron health in the lab and saved mice with the 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 an injection, said lead inventor Professor Matthew Disney, Ph.D., chair of the chemistry department at UF Scripps. Importantly, the experiments showed that the compound is small enough to cross the blood-brain barrier, a hurdle other approaches have failed to overcome, he said.
Amyotrophic lateral sclerosis, or ALS, progressively destroys the neurons that control muscles, leading to worsening muscle wasting and ultimately death. The mutation, a leading cause of inherited ALS, is referred to as “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, resulting in changes in personality, behavior and language, ultimately leading to death.
The C9orf72 mutation features an expanded 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 stretch of RNA is present, it causes the production of toxic proteins that disease and eventually kill the affected neurons. The compound developed by the Disney lab targets the RNA that carries those genetic instructions, thus preventing the toxic proteins from being assembled in cells.
“The compound works by binding to and using natural cellular processes to eliminate disease-causing RNA, alerting the cell’s degradation machinery to dispose of it as waste,” said Disney.
This approach could conceivably work for other untreatable neurological diseases in which toxic RNA plays a role, he added.
The paper’s first author is Jessica Bush, a graduate student of 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 from the Calibr library at Scripps Research, which includes 11,000 drug-like molecules,” Bush said.
From that initial screen, they identified 69 compounds that inhibited translation of the toxic C9 mutation. They then further 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 on neurons derived from ALS patients and in vivo models showed that compound 1 selectively and avidly binds toxic RNA, forcing 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 donated skin samples for research purposes. These skin cells were genetically converted into stem cells, after which the Disney team treated the cells for several months to turn them into neurons.
“Four different patient cells were used for the evaluation, and they showed dose-dependent reductions in known ALS markers without having off-target effects,” Bush said.
They also tested the compound in mice bred to have the C9orf72 mutation and exhibit behaviors and blood markers typical of ALS. The mice were treated daily for two weeks, after which the mice showed significantly reduced markers for disease 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. Evidence so far shows that this approach represents a major advance in RNA-based drug discovery, she said.
“We show for the first time that it is possible to create brain-penetrating molecules that clear out toxic gene products,” Disney said. “The fact that we have highlighted this in ALS demonstrates that this may be a general approach for other neurological diseases, including Huntington’s, forms of muscular dystrophy and others.”
reference: Bush JA, Meyer SM, Fuerst R, et al. A small molecule targeting blood penetrating RNA in the brain triggers the elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome. PNAS. 2022;119(48):e2210532119. doi: 10.1073/pnas.2210532119
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