Experimental treatment slows prion disease and prolongs life of mice

Scientists using experimental therapy have slowed the progression of scrapie, a degenerative disease of the central nervous system caused by prions, in laboratory mice and have greatly prolonged rodent life, according to a new report published in JCI Insight. Scientists used antisense oligonucleotides (ASOs), synthetic compounds that inhibit the formation of specific proteins.

Prion diseases occur when normally harmless prion protein molecules become abnormal and collect into clusters and filaments in the body, including the brain. It is thought that diseases are always fatal. Scrapie, which affects sheep and goats and can be adapted to rodents, is closely related to human prion diseases such as Creutzfeldt-Jakob disease, which is currently incurable. For example, scrapie is a valuable experimental model for the development of treatments for human prion disease.

In these studies, scientists from the National Institutes of Health and their colleagues injected ASO into the cerebrospinal fluid of mice already infected with scrapie or contaminated with scrapie proteins a few weeks after injection. Ionis Pharmaceuticals has specifically designed ASO1 and ASO2 to reduce the intake of normal prion proteins in rodents. Rodent studies using different doses of ASO1 and ASO2 were conducted at Rocky Mountain Laboratories (RML) Laboratories in Hamilton, Montana (belonging to the National Institute of Allergy and Infectious Diseases). NIH) and at the Broad Institute in Cambridge, Mbadachusetts.

RML scientists injected ASO1 or ASO2 to mice 14 days before infecting them with scrapie, then seven or 15 weeks after the infection. ASO1 treated mice showed no clinical signs of disease for an average of 250 days, 82% more than untreated mice (137 days) and 81% longer than untreated mice (259 vs. 143 days). . ASO2-treated mice showed no clinical signs of disease for 272 days on average, 99% longer than untreated mice (137 days) and lived 98% longer than untreated mice (283 days vs. 143 days). In the Broad Institute experiments, the mice received ASO1 or ASO2 two weeks before scrapie infection and seven weeks after infection. Both ASOs delayed weight loss in rodents. Both ASO1 and ASO2-treated mice lived longer than untreated mice, with 61% (274 days vs. 170 days) and 76% (300 vs. 170 days), respectively.

The RML group also tested ASOs against established prion disease, treating mice 17 weeks after their scrapie infection, which is close to the onset of clinical signs. Mice treated with ASO1 showed no clinical signs of disease for an average of 189 days, 33% longer than untreated mice (142 days). They also showed a slower progression of the disease and lived 55% longer than the untreated mice (244 days vs. 157 days). ASO2 did not have any beneficial effects.

The researchers plan to extend their ASO scrapie studies to human prion diseases. Other researchers have found promising initial results in humans with OSA directed against Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Huntington's disease.