Repairing Genetic Mutations in Neurological Diseases with RNA Targeting Strategy

UF Scripps Biomedical Research scientists have developed a potential drug for a major cause of neurological diseases, including amyotrophic lateral sclerosis (ALS) and dementia by removing disease-causing RNA segments. The compound restored the health of neurons in the lab and rescued mice with the disease. Most importantly, the compound is small enough to cross the blood-brain barrier, making it look promising for human use.

Proceedings of the National Academy of Sciences published the article on November 21. The team designed the drug as a pill or injection, according to the lead inventor, professor Matthew Disney, Ph.D., chair of the UF Scripps chemistry department.  

Related Article: Canada Approves Amylyx’s Experimental ALS Drug

The Complexities of Neurological Diseases

ALS is a rare neurological disease that primarily affects the neurons responsible for controlling voluntary muscle movement. The early symptoms of ALS usually include muscle weakness or stiffness. The disease is progressive, and eventually, individuals lose their strength and the ability to speak, eat, move, and even breathe. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the symptoms’ first appearance. Currently, no treatment is available for ALS to halt or reverse the progression of the disease.

One of the main causes of inherited ALS is a gene mutation of C9orf72. Other than ALS, this mutation also results in frontotemporal dementia, a brain disorder in which the frontal and temporal lobes of the brain shrink, causing personality, behavior, and language changes and eventually leading to death.  

The C9orf72 mutation has an extended repeat of the genetic code GGGGCC on chromosome 9, which can duplicate between 65 and 10,000 times. This mutated stretch of RNA produces toxic proteins that weaken and eventually kill affected neurons. The novel compound introduced in this study targets the RNA that carries these genetic instructions, preventing the toxic proteins from being assembled in cells.

Potential Therapy for Neurological Disease

Scientists developed the neuron model from skin samples donated by ALS patients at the Johns Hopkins University School of Medicine’s Laboratory for Neurodegenerative Research. The study used four different patients’ cells for the assessment, and they all showed a dose-dependent reduction in known ALS markers without off-target effects. 

In the case of animal models, scientists test the compound in mice bred with the C9orf72 mutation. The mice were treated daily for two weeks and displayed significantly reduced markers for disease and improved health at the end of the study.

To sum up, this study is the first to develop brain-penetrant molecules that eliminate toxic gene products. The molecule can be a general approach for other neurological diseases, including Huntington’s disease, a form of muscular dystrophy in addition to ALS. The next focus for scientists is to study further the compound’s effects on cellular health and rodent models of C9 ALS.

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Author

Nai Ye Yeat