Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease

In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).

Anle138b strongly inhibited all prion strains tested including BSE-derived and human prions.?Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein.?Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo.?Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration.

anle138b was administered orally in DMSO/peanut butter as described above.?In a first set of experiments, 5 mg anle138b were given once daily starting either at day 80 or day 120 post i.c. infection.?Animals of each treatment group were monitored daily for signs of disease by trained animal caretakers from day 80 post infection.?The animals were sacrificed, when they had reached the terminal stage of the disease based on clinical signs (ataxia, tremor, difficulty in righting up from a position lying on its back and tail stiffness).?Typically the disease progress through the terminal stage will lead to the death of the animal within 1 or 2 days.?In addition, groups of four mice per experimental group were sacrificed at predefined time points. From all animals, one brain hemisphere and one half of the spleen were freshly frozen at 80 C for biochemical analysis.?The other hemisphere and the remaining half of the spleen as well as all inner organs were fixed in 4 % formaldehyde solution for histological analysis.?In a further experiment, treatment with anle138b was started on the day of i.c. infection with a dose of 5 mg anle138b twice daily.