The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset
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KeywordsPrion Disease Terminal Disease Rotarod Performance aSyn Oligomer Parkinson Mouse
Parkinson’s disease (PD) is characterized by the deposition of aggregated alpha-synuclein (aSyn). Recent evidence suggests that oligomers formed in the aggregation process constitute the main toxic species causing neurodegeneration. Recently, we reported that the oligomer modulator “anle138b” [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole] is capable of prolonging the survival of prion-infected mice and of various animal models of PD . Anle138b blocked formation and accumulation of aSyn oligomers in the brain, reduced disease-associated motor deficits, and led to prolonged disease-free survival . These findings support the following hypotheses: (i) oligomers formed in the aggregation process of disease-specific proteins, such as prion protein in prion diseases or aSyn in synucleinopathies, constitute the main toxic species involved in neuronal cell death [1, 2, 3] and (ii) these oligomers are a suitable target for disease modification .
While we could show that anle138b is capable of prolonging the survival of prion-infected mice even after onset of symptoms, it had remained unclear whether anle138b is also effective in animal models of PD when treatment is started secondary to clinical disease onset. The effect of a compound after onset of symptoms is an important prerequisite for its use as a disease-modifying therapy in humans, because clinicians rely on symptoms to establish a diagnosis. Even if early diagnosis from pre-locomotor symptoms such as olfaction problems or aSyn deposits in the gut in combination with imaging or other biomarkers is expected to be available in the future, which would allow earlier initiation of neuroprotective treatment, not all patients may be identified with such a diagnosis. In order to evaluate a potential use of anle138b as a disease-modifying PD therapy, we set out to test the effect of treatment with anle138b after onset of symptoms in a transgenic PD model based on neuronal expression of human A30P-aSyn . Onset of symptoms in the A30P-aSyn mouse model was described by us in the initial publication . In brief, we observed a prodromal disease phase beginning at about 300 days of life with fluctuations in rotarod performance and, beginning at around 350 days of life, a failure to gain body weight . Thus, in the current experiment oral treatment with anle138b was started from the 50th week of life, the time point at which these two clinical signs were present in the previous experiment. The dose of anle138b remained unchanged. Hence, mice received 5 mg anle138b dissolved in 10 μl DMSO mixed with 200 μl peanut butter two times per day. In parallel, a group of transgenic mice was placebo-treated with 10 μl DMSO mixed with 200 μl peanut butter twice daily. Disease progression was monitored by measurements of rotarod performance. As in the previous publication, onset of terminal disease (“disease free survival”) was defined by a decrease in motor performance below mean − 3 SD of the wild-type control mice .
All in all, these data show that treatment with the oligomer modulator anle138b started in the symptomatic disease phase at 50 weeks of life has a significant effect on survival until onset of terminal disease. This is a key prerequisite for disease modification and thus holds promise for a disease-modifying effect of anle138b in PD patients.
This work was supported by the Novartis prize for therapeutical research (to JL), the Munich Cluster for Systems Neurology (SyNergy), by the Lüneburg Foundation, the Max Planck Society (to CG) and the DFG (CNMPB). Some of the authors (SR, AL, CG, and AG) are inventors in a patent application related to the novel compound presented in this manuscript. We thank Katie Ogston for language editing the manuscript.
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