Scientists using experimental treatments have slowed the progression of scrapie, degenerative disease of the central nerve caused by prions in laboratory mice, and have significantly extended the life of rodents, according to a new report in JCI Insight, Scientists use antisense oligonucleotides (ASOs), synthetic compounds that inhibit the formation of specific proteins.
Prion diseases occur when normally harmless prion protein molecules become abnormal and accumulate in clumps and filaments in the body, including the brain. Diseases are always thought to be fatal. Scrapie, which affects sheep and goats and can be adapted to rodents, is closely linked to prion diseases in humans, such as Kreuzfeld-Jakob disease, which is currently incurable. Thus, scrapie is a valuable experimental model for the development of therapies in human prion diseases.
In the studies, researchers from the National Institutes of Health and their colleagues injected ASOs into the spinal fluid of mice that were already infected with scrapie or that had been challenged with scrapie proteins within weeks of the injection. Ionis Pharmaceuticals has specifically developed ASO1 and ASO2 to reduce rodents' supply of normal prion protein. Rodent studies using different doses of ASO1 and ASO2 were conducted at Rocky Mountain Laboratories (RML) in Hamilton, Montana, (part of the National Institute of Allergy and Infectious Diseases of the NIH) and at the Greater Cambridge Institute, Massachusetts.
RML scientists injected either ASO1 or ASO2 into mice 14 days before scraping them and then seven or 15 weeks after the infection. Mice treated with ASO1 showed no clinical signs of disease on average 250 days or 82% longer than untreated mice (137 days), and they lived 81% longer than untreated mice (259 days versus 143 days). Mice treated with ASO2 showed no clinical signs of disease for an average of 272 days, or 99% longer than untreated mice (137 days), and they lived 98% longer than untreated mice (283 days versus 143 days). In Wide Institute experiments, mice received either ASO1 or ASO2 2 weeks before scraping and then seven weeks after infection. Both ASOs delayed the weight loss of rodents. Mice treated with ASO1 and ASO2 lived longer than untreated mice, respectively, with 61% (274 days versus 170 days) and 76% (300 days versus 170 days).
The RML group also tested ASOs against established prion disease, treating mice 17 weeks after scrapes were infected – near the onset of clinical signs. Mice treated with ASO1 showed no signs of clinical disease for a median of 189 days, or 33% longer than untreated mice (142 days). They also show a slower progression of the disease and live 55% longer than untreated mice (244 days versus 157 days). ASO2 has no beneficial effect.
The researchers plan to extend their research on ASO scrapes to human prion diseases. Other researchers have seen promising initial results in people with ASO against Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Huntington's disease.
G. Raymond, et al. Antisense oligonucleotides prolong the survival of prion-infected mice. JCI Insight, Doi: 10.1172 / jci.insight.131175 (2019).
Byron Caughey, Ph.D., Senior Researcher at the NIAID Resistant Viral Laboratory, is available for comment on this study.
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