AD/PD 2024 – Parkinson Disease (Neuroprotection)

NX210c PEPTIDE: A PROMISING DRUG CANDIDATE FOR NEUROPROTECTION IN PARKINSON’S DISEASE Download Poster Sighild Lemarchant 1 , Juliette Le Douce 1 , Alexandre Henriques 2 , Noëlle Callizot 2 , Yann Godfrin 1,3 1 Axoltis Pharma, Lyon, France 2 Neuro-Sys, Gardanne, France 3 Godfrin Life-Sciences, Caluire-et-Cuire, France Objectives PD is characterized by the accumulation of α-synuclein and blood-brain barrier disruption, thereby contributing to the loss of dopaminergic neurons in the substantia nigra. Here, we have evaluated the effect of a subcommissural organ-spondin-derived peptide (NX210c) on PD progression using in vitro and in vivo rat models. Methods Primary rat dopaminergic neurons were exposed for 48h to human α-synuclein and treated simultaneously with NX210c (100, 250, 500 µg/mL) or its vehicle (water), or to 6-OHDA and then treated for 2h with NX210c or its vehicle. Neuronal survival, neurite growth, microglial activation and/or α-synuclein aggregation were evaluated by immunocytochemistry. Sprague Dawley rats were subjected to an injection of AAV1/2-hA53T-α-synuclein or an empty AAV (control) in the substantia nigra, and treated 2 days later with NX210c at 2.5, 5 or 10 mg/kg and then once a day for 41 days. Rats were sacrificed on D42 to measure dopamine levels (LC-MS/MS), dopamine transporters (autoradiography), and α-synuclein aggregation (ELISA) in the striatum. Results NX210c reduced α-synuclein-induced neurite network retraction, neuronal death and microglial activation in dopaminergic neuron cultures, when applied in parallel of α-synuclein regardless of the dose used. Dopaminergic neurons were also protected from 6-OHDA when post-treated for 2h with NX210c at 500 µg/mL, likely due to the decrease in α-synuclein aggregation (-71%, p=0.004, n=4-5). In vivo , daily treatment with NX210c at 5 mg/kg significantly increased dopamine levels and its transporters in the striatum compared with that of untreated PD rats (n=9-11, p<0.05). No effect was observed at 2.5 and 10 mg/kg. In this model, NX210c did not reduce α-synuclein aggregation (p>0.05). Conclusions NX210c is a promising drug candidate for reducing neuropathological changes in PD, notably the loss of dopaminergic neurons.

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