Objective: (1) Determine whether oral ATH434 improves motor performance in a non-human primate hemiparkinasonian model when administered after symptom onset. (2) Relate observations to changes in brain iron, preservation of substantia nigra (SN) tyrosine hydroxylase positive (TH+) neurons, and nigrostriatal integrity.
Background: ATH434 is a novel iron binding drug candidate currently in Phase 2 clinical trials for Multiple System Atrophy (MSA)[1]. In Parkinson’s disease[2] and MSA[3,4] mouse models, ATH434 reduced disease-related excess iron, oxidative stress markers, and aggregated alpha-synuclein. ATH434 also improved nigrostriatal pathway integrity and motor performance. With moderate affinities for Fe2+ and Fe3+, ATH434 is postulated to redistribute excess labile cellular iron, primarily the reactive Fe2+ form, facilitating export from cells or sequestering it safely. Unlike high-affinity Fe3+ chelators approved for iron overload, ATH434’s moderate iron affinity precludes it from interfering with endogenous iron trafficking proteins such as transferrin.
Method: Young male macaques received a single right carotid MPTP infusion (Day 0) followed by daily oral doses of vehicle or ATH434 (3mg/kg/day or 10 mg/kg/day) from Day 3 to Weeks 12-14 (final n=2-3/group). Parkinson Behavior Rating Scale (PBRS) scores were recorded pre-treatment (Day 2), and during Weeks 4, 8, and 12. Terminal endpoints included SN iron (mass spectrometry), TH+ SN neurons (immunocytochemistry), dorsal striatal dopamine transporter (DAT) density (PET), and synaptophysin (western blot).
Results: Pre-treatment left side specific, generalized motor, and generalized behavior scores of the PBRS indicated significant parkinsonism in all macaques. Striatal DAT confirmed similar lesion sizes across groups. At Week 12, all ATH434-treated and 1 vehicle-treated macaque had improved or stabilized scores; the remaining 2 vehicle-treated macaques demonstrated worsening symptoms. Changes in TH+ SN neuron counts were not significant. Reduced parkinsonian indices clustered with increased right-side striatal synaptophysin and reduced right-side SN iron.
Conclusion: ATH434 improved motor performance in MPTP-injured primates in this small study. Efficacy may reflect reduction or sequestration of labile iron in areas of pathology, facilitating neurite recovery in the nigrostriatal pathway by reducing iron-mediated oxidative damage[5].
References: [1] https://www.clinicaltrials.gov/study/NCT05109091, https://www.clinicaltrials.gov/study/NCT05864365\
[2] Finkelstein DI, Billings JL, Adlard PA, et al. The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. Acta Neuropathol Commun. 2017 5:53. doi: 10.1186/s40478-017-0456-2
[3] Heras-Garvin A, Refolo V, Schmidt C, et al. ATH434 Reduces α-Synuclein-Related Neurodegeneration in a Murine Model of Multiple System Atrophy. Mov Disord. 2021 36:2605-2614. doi: 10.1002/mds.28714
[4] Finkelstein DI, Shukla JJ, Cherny RA et al. The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy. J Parkinsons Dis. 2022 12:105-115. doi: 10.3233/JPD-212877
[5] Shi L, Huang C, Luo Q, et al. Clioquinol improves motor and non-motor deficits in MPTP-induced monkey model of Parkinson’s disease through AKT/mTOR pathway. Aging 2020 12:9515-9533. doi: 10.18632/aging.103225
To cite this abstract in AMA style:
M. Bradbury, M. Aumann, D. Claassen, D. Finkelstein. Effects of ATH434, a Clinical-Phase Small Molecule with Moderate Affinity for Iron, in a Parkinson’s Disease Model in Macaques [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/effects-of-ath434-a-clinical-phase-small-molecule-with-moderate-affinity-for-iron-in-a-parkinsons-disease-model-in-macaques/. Accessed October 5, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-ath434-a-clinical-phase-small-molecule-with-moderate-affinity-for-iron-in-a-parkinsons-disease-model-in-macaques/