Abstract Details

Title ATH434 Preserves Dopaminergic Neurons, Reduces a-synuclein Oligomerization, and Improves Motor Function in a Transgenic Murine Multiple System Atrophy Model

Topic Movement Disorders

Presentation(s) S27 - Movement Disorders: Basic Science (2:32 PM-2:40 PM)

Poster/Presentation
Number 004

Objective To characterize ATH434 for disease modification in a mouse model of multiple system atrophy (MSA)

Background MSA, a fatal neurodegenerative disorder with no currently approved treatments, is characterized by aggregated α-synuclein in oligodendrocytes and elevated iron in subcortical motor nuclei including the substantia nigra (SN). ATH434 is a novel, brain-penetrant, orally bioavailable small molecule inhibitor of α-synuclein aggregation that binds iron with a moderate affinity that is competitive with α-synuclein but not iron-regulatory proteins. ATH434 has previously shown efficacy in the PLP-α-syn transgenic mouse model of MSA (Finkelstein, 2019). ATH434 is well-tolerated and displays dose-dependent pharmacokinetics in healthy volunteers with steady-state CSF concentrations exceeding those associated with efficacy in MSA-model mice (Stamler, 2019). In the present study, ATH434 was evaluated in the MSA mouse model for changes in neuron counts, in oligomeric α-synuclein, and for altered performance in a motor task for SN functioning.

Design/Methods Six-month old MSA mice received ATH434 in diet or control diet for six months. Motor behavior was evaluated on a modified (“challenging”) balance beam test. Brains were evaluated by immunocytochemistry for tyrosine hydroxylase staining of SN neuronal soma and DARRP-32 staining of striatal medium spiny neurons. Midbrain monomeric and oligomeric α-synuclein content was quantified by Western blot.

Results Supporting previous findings, ATH434-treated MSA mice demonstrated: improved motor performance as compared to control (p<0.05); preserved total and dopaminergic neurons in the SN as well as total and DARPP-32-positive neurons in striatum (each p<0.001); and a reduced proportion of oligomeric α-synuclein (p<0.05). Preservation of striatal neurons correlated strongly with attenuation of α-synuclein oligomerization (p<0.0001).

Conclusions Our findings demonstrate the beneficial disease-modifying effect of ATH434 in oligodendroglial α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the MSA mouse model. Paired with the favorable human pharmacokinetic profile (Stamler, 2019), these results support the development of ATH434 for MSA.

Authors/Disclosures
Margaret Bradbury (Alterity Therpeutics) PRESENTER	Margaret Bradbury has received personal compensation for serving as an employee of Alterity Therapeutics. The institution of Margaret Bradbury has received research support from Alterity Therapeutics.
	No disclosure on file
	No disclosure on file
David A. Stamler, MD (Alterity Therapeutics)	Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has stock in Alterity Therapeutics.
	No disclosure on file

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