Objective: To assess the effects of nilotinib on motor behavior, α-synuclein burden and surrogate markers of neurodegeneration in a transgenic mouse model of multiple system atrophy (MSA).

Background: The pathological hallmark of MSA is the presence of α-synuclein bearing glial cytoplasmic inclusions. Treatment is available for some symptoms, in particular autonomic dysfunction, while disease modification remains an urgent unmet need. Activation of the tyrosine kinase c-Abl protein is increased in Parkinson’s disease (PD) and alpha-synuclein has been identified as one of its substrates. Through C-Abl inhibition, nilotinib (a commercially available treatment for a type of leukemia) is thought to potentially counteract α-synuclein accumulation and to protect neurons from degeneration. In this regard, positive effects of nilotinib on the neurodegenerative process have been reported in preclinical models of PD. The aim of this study was to evaluate the effects of nilotinib in PLP-SYN mice, a transgenic mouse model of MSA.

Methods: Wild-type (WT) mice received daily intraperitoneal injections of vehicle and transgenic PLP-SYN received daily intraperitoneal injections of either vehicle, nilotinib 1mg/kg or 10mg/kg, for 12 weeks since age 6 weeks. Motor behavior was assessed at baseline and every 4 weeks until termination. The histopathological analysis included cell survival in the substantia nigra pars compacta (SNpc) as assessed by the number of tyrosine hydroxylase and Nissl positive neurons. Immunoblotting was performed to measure α-synuclein load.

Results: Nilotinib was safe and well tolerated at both doses by PLP-SYN mice. There was no difference in motor performance between the different treatment groups of PLP-SYN mice. As expected, placebo-treated PLP-SYN mice showed dopaminergic cell loss in the SNpc compared to WT mice, while nilotinib failed to protect neurons from degeneration and to attenuate α-synuclein burden in PLP-SYN mice.

Conclusions: Nilotinib failed to demonstrate positive effects in a transgenic mouse model of MSA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nilotinib-for-treating-msa-a-preclinical-proof-of-concept-study/