Category: Parkinson's Disease (Other)
Objective: Assess the nonclinical efficacy and safety of C16-conjugated siRNAs targeting SNCA mRNA (SNCA siRNA).
Background: Parkinson’s disease is a neurodegenerative disorder with an estimated global burden of 10 million cases and no available disease-modifying therapies. It is characterized by aggregation of alpha-synuclein protein (⍺Syn; encoded by SNCA) and the consequent loss of several neuronal populations, including substantia nigra dopaminergic neurons. Nigrostriatal degeneration reduces dopaminergic signaling in the dorsal striatum leading to characteristic motor impairments. SNCA gene multiplications, gain-of-function mutations (e.g. A53T), and SNCA-related genetic risk in genome-wide studies, point to the critical role of SNCA in familial and idiopathic disease pathogenesis. Therapeutic strategies aimed at reducing ⍺Syn are hypothesized to slow disease progression.
Method: Transgenic mice expressing human A53T SNCA were injected with ⍺Syn fibrils in the dorsal striatum and received a single intracerebroventricular (ICV) injection of SNCA siRNA after disease onset and were monitored for disease progression. To assess PK/PD relationships and toxicity, monkeys were dosed with ALN‑SNCA, our lead SNCA siRNA, via intrathecal (IT) dosing.
Results: In mice, ICV injection of SNCA siRNA led to a robust knock-down (KD) of SNCA in the CNS. SNCA KD prevented accumulation and spread of pathological ⍺Syn across multiple brain regions and cleared established ⍺Syn aggregates. It also reduced astrogliosis and microgliosis, prevented loss of dopaminergic neurons, and prevented motor deficits and progression to paralysis. In monkeys, a single IT dose of ALN-SNCA produced a dose-dependent reduction in ⍺Syn. Low and high doses demonstrated maximal mean reduction of ≥41% and ≥60% in CSF and up to 68% and 93% in various CNS tissues, respectively. In a GLP repeat-dose toxicology study in monkeys, the highest dose was established as the no-observed-adverse-effect level. Dose-related ⍺Syn reduction in CNS tissues was sustained over the duration of the monkey studies.
Conclusion: These studies demonstrate a robust nonclinical safety profile and disease-modifying potential of SNCA siRNA for Parkinson’s disease supporting the clinical development of ALN-SNCA.
To cite this abstract in AMA style:
P. Aimé-Wilson, N. Keating, C. Galligan, C. Brown, M. Gao, P. Mookherjee, S. Godin, J. Dave, M. Retter, A. Castoreno, K. Brown, M. Ahmed, A. Avbersek, C. Kyratsous. SNCA-Targeting RNAi Therapeutics Prevent Disease Progression in a Synucleinopathy Mouse Model and Enable Robust, Prolonged, and Safe Alpha-Synuclein Protein Reduction in the Cynomolgus Monkey Central Nervous System [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/snca-targeting-rnai-therapeutics-prevent-disease-progression-in-a-synucleinopathy-mouse-model-and-enable-robust-prolonged-and-safe-alpha-synuclein-protein-reduction-in-the-cynomolgus-monkey-central/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/snca-targeting-rnai-therapeutics-prevent-disease-progression-in-a-synucleinopathy-mouse-model-and-enable-robust-prolonged-and-safe-alpha-synuclein-protein-reduction-in-the-cynomolgus-monkey-central/