Stamler's poster in the ANA 2020 meeting, page-2

This the abstract of Stefanova et al


500. PBT434 Preserves Dopaminergic Neurons, Reduces
α-Synuclein Oligomerization, and Improves Motor
Function in a Transgenic Murine Multiple System
Atrophy Model
Antonio Heras-Garvin, PhD1
, Violetta Refolo, PhD1
,
Claudio Schmidt, BSc1
, Margaret Bradbury, PhD2
, David
Stamler, MD2
, Nadia Stefanova, MD, PhD, DSc1
. 1
Medical
University of Innsbruck, Innsbruck, Austria, 2
Alterity
Therapeutics, Newark, CA, USA.
Objective: To characterize PBT434 for disease modification
in a mouse model of multiple system atrophy (MSA).
Background: MSA is a fatal neurodegenerative disorder
characterized by aggregated α-synuclein in oligodendrocytes
and accompanied by neuropathological indicators of oxidative
stress and elevated iron in subcortical motor nuclei such as
the substantia nigra (SN). Key features of MSA are replicated
in the PLP-α-syn transgenic mouse, including progressive
striatonigral degeneration and motor deterioration (Refolo
et al. Acta Neuropathologica Communications 2018). There
are currently no approved treatments for MSA. PBT434 is a
novel, orally bioavailable brain penetrant small molecule
inhibitor of α-synuclein aggregation with an iron binding
affinity competitive for α-synuclein but not for endogenous
iron trafficking proteins. In the PLP-α-syn transgenic mouse,
PBT434 reduced glial cell inclusions, preserved SN neurons,
and improved motor function (Finkelstein American Academy of Neurology [AAN] Annual Meeting, 2019); PBT434
also preserved neurons in multiple Parkinson Disease models
(Finkelstein Acta Neuropathologica Communications 2017).
In a recently completed Phase 1 study in healthy volunteers,
orally administered PBT434 was well-tolerated and displayed
dose-dependent pharmacokinetics (Stamler, AAN Annual
Meeting, 2020). In the current study, PBT434 was evaluated
in the PLP-α-syn transgenic mouse for changes in the number of dopaminergic neurons, in oligomeric α-synuclein, and
for altered performance in a motor task for subtantia nigral
functioning.
Design/Methods: Six-month old PLP-α-syn transgenic
mice received PBT434 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: Consistent with previous findings, PBT434-
treated MSA mice demonstrated improved motor performance, with fewer slips per step on the balance beam as compared to control (p<0.05). Extending recent findings,
PBT434 preserved dopaminergic neurons in the SN pars
compacta and DARPP-32-positive neurons in striatum
(p<0.001). PBT434 reduced the prevalence of oligomeric
α-synuclein (p<0.05). Preservation of striatal neurons was
strongly correlated with attenuation of α-synuclein oligomerization (p<0.0001).
Conclusion: Our findings demonstrate the beneficial disease-modifying effect of PBT434 in oligodendroglial
α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the PLP-α-syn transgenic mouse.
Paired with the favorable human pharmacokinetic profile,
these results support the development of PBT434 for MSA.