UF Scripps Biomedical Research scientists 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 72 open reading frame” 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.”
The study, “A small molecule RNA-targeted entry into blood and brain triggers elimination of r(G4C2)exp in c9ALS/FTD via nuclear RNA exosome,” appears in Proceedings of the National Academy of Sciences this week. 21, 2022. Authors include Samantha M. Meyer, Rita Fuerst, Yuquan Tong, Yue Li, Haruo Aikawa, Patrick RA Zanon, Quentin MR Gibaut, Alicia Angelbello, Tania Gendron, Yong -Jie Zhang, Torben Heick Jensen, and Jessica Childs- Disney.
This study was funded by the National Institutes of Health (NIH P01 NS099114 to MDD and LP; DP1 NS096898 and R35 NS116846 to MDD; and R35 NS097273 to LP); Target SLA (to MDD); the Nelson Family Fund (at MDD); the First Family Fund (at MDD); and the Scheller Graduate Scholarship (to SMM). Declaration of competing interests: MDD is one of the founders of Expansion Therapeutics.
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