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Next generation ALS drug silences inherited form of the disease in animal models

Preclinical study suggests drug may be ready for early stage clinical trials

Date:
July 26, 2018
Source:
NIH/National Institute of Neurological Disorders and Stroke
Summary:
Researchers delayed signs of amyotrophic lateral sclerosis (ALS) in rodents by injecting them with a second-generation drug designed to silence the gene, superoxide dismutase 1 (SOD1). The results suggest the newer version of the drug may be effective at treating an inherited form of the disease caused by mutations in SOD1.
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NIH-funded researchers delayed signs of amyotrophic lateral sclerosis (ALS) in rodents by injecting them with a second-generation drug designed to silence the gene, superoxide dismutase 1 (SOD1). The results, published in the Journal of Clinical Investigation, suggest the newer version of the drug may be effective at treating an inherited form of the disease caused by mutations in SOD1. Currently, the drug is being tested in an ALS clinical trial (NCT02623699).

ALS destroys motor neurons responsible for activating muscles, causing patients to rapidly lose muscle strength and their ability to speak, swallow, move, and breathe. Most die within 3-5 years of symptom onset. Previous studies suggested that a gene therapy drug, called an antisense oligonucleotide, could be used to treat a form of ALS caused by mutations in the gene SOD1. These drugs turned off SOD1 by latching onto versions the gene encoded in messenger RNA (mRNA), tagging them for disposal and preventing SOD1 protein production.

Using rats and mice genetically modified to carry normal or disease-mutant versions of human SOD1, a team of researchers led by Timothy M. Miller, M.D., Ph.D., Washington University, St. Louis, MO, discovered that newer versions of the drug may be more effective at treating ALS than the earlier one that had been tested in a phase 1 clinical trial. For instance, injections of the newer versions were more efficient at reducing normal, human SOD1 mRNA levels in rats and mice and they helped rats, genetically modified to carry a disease-causing mutation in SOD1, live much longer than previous versions of the drug. Injections of the new drugs also delayed the age at which mice carrying a disease-mutant SOD1 gene had trouble balancing on a rotating rod and appeared to prevent muscle weakness and loss of connections between nerves and muscles, suggesting it could treat the muscle activation problems caused by ALS. These and other results were the basis for a current phase 1 clinical trial testing the next generation drug in ALS patients (NCT02623699).


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Materials provided by NIH/National Institute of Neurological Disorders and Stroke. Note: Content may be edited for style and length.


Journal Reference:

  1. Alex McCampbell, Tracy Cole, Amy J. Wegener, Giulio S. Tomassy, Amy Setnicka, Brandon J. Farley, Kathleen M. Schoch, Mariah L. Hoye, Mark Shabsovich, Linhong Sun, Yi Luo, Mingdi Zhang, Sai Thankamony, David W. Salzman, Merit Cudkowicz, Danielle L. Graham, C. Frank Bennett, Holly B. Kordasiewicz, Eric E. Swayze, Timothy M. Miller. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. Journal of Clinical Investigation, 2018; DOI: 10.1172/JCI99081

Cite This Page:

NIH/National Institute of Neurological Disorders and Stroke. "Next generation ALS drug silences inherited form of the disease in animal models." ScienceDaily. ScienceDaily, 26 July 2018. <www.sciencedaily.com/releases/2018/07/180726162043.htm>.
NIH/National Institute of Neurological Disorders and Stroke. (2018, July 26). Next generation ALS drug silences inherited form of the disease in animal models. ScienceDaily. Retrieved December 8, 2024 from www.sciencedaily.com/releases/2018/07/180726162043.htm
NIH/National Institute of Neurological Disorders and Stroke. "Next generation ALS drug silences inherited form of the disease in animal models." ScienceDaily. www.sciencedaily.com/releases/2018/07/180726162043.htm (accessed December 8, 2024).

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