AD/PD 2024 – Parkinson Disease (BBB restoration)

NX210c PEPTIDE: A PROMISING DRUG CANDIDATE FOR BLOOD-BRAIN BARRIER REPAIR IN PARKINSON’S DISEASE

Nicolas Rebergue¹, Chris Greene², Matthew Campbell², Gwen Fewell³, Supriya Mahajan⁴, Damir Janigro⁴, Juliette Le Douce¹, Sébastien Marie¹, Annette Janus¹, Yann Godfrin^1,5, Sighild Lemarchant¹

Objectives

Recent works show that blood-brain barrier (BBB) leakage represents a disease-driving feature of PD, as shown by the reduction of tight junction proteins and the increased BBB paracellular permeability in animal models. Accordingly, BBB disruption was also shown in the substantia nigra of PD patients. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c) known to be beneficial in PD models, on BBB integrity in vitro and in vivo.

Methods/Results

Mouse endothelial cell (EC) monolayers (bEnd.3) and human BBBs (EC, astrocytes, pericytes) in static or microfluidic conditions, were treated with NX210c (1-100μM), or its vehicle (water). In mouse EC, NX210c induced a transient increase in occludin levels after 24h treatment (+37%, 100µM; western-blot). Claudin-5 levels were also increased after 24h (+43%, 100µM) and 72h (immunocytochemistry). Accordingly, NX210c decreased by half the permeability to a 40 kDa-FITC-Dextran and increased transendothelial electrical resistance (TEER). In the human static BBB model, NX210c increased by 30% the TEER at 100µM after 3 and 5 days. NX210c also increased TEER in the human 3D dynamic BBB model at 100µM after 4h, and reduced the permeability to a 4 kDa-FITC-dextran.

3- and 21-month-old mice were treated intraperitoneally with NX210c at 10mg/kg or its vehicle for 5 days once a day and brains collected at day6. NX210c restored aging-induced reduction of claudin-5 and occludin levels in the cortex and/or hippocampus. This is in alignment with positive signals of BBB repair after repeated intravenous injections of NX210c in elderly healthy volunteers in a phase 1b clinical trial.

Conclusions

NX210c is a promising drug candidate for modifying PD course, notably by reducing BBB leakage. Therefore, we are now evaluating if NX210c promotes BBB repair in a PD mouse model.