WFNR 2024 – Amyotrophic Lateral Sclerosis
NX210c drug candidate peptide improves motor function and prolongs survival in the SOD1G93A mouse model of amyotrophic lateral sclerosis
Sighild Lemarchant1, Liam Beckett2, Irina Belaya3, Jaan Korpikoski2, Katja M. Kanninen3, Merja H. Voutilainen2, Yann Godfrin1,4
1Axoltis Pharma, Lyon, France
2HiLife, University of Helsinki, Helsinki, Finland
3AI Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
4Godfrin Life-Sciences, Caluire-et-Cuire, France
NX210c is a short cyclic peptide derived from the subcommissural organ-spondin that displays in vitro beneficial effects on several aspects of ALS pathogenesis such as on blood-brain barrier permeability and neuronal death induced by glutamate excitotoxicity. Therefore, the aim of this study was to evaluate the therapeutic effect of NX210c in the SOD1mouse model of ALS.
Female SOD1G93A mice were treated daily with intraperitoneal injections of vehicle or different doses of NX210c (2.5, 5 or 10 mg/kg) from 90 days old. The static rods test was performed every other week to evaluate motor deficits. Briefly, mice were placed with their back facing the clamped end of the rod. The orientation time to turn back and the travel time to walk the 60 cm back to the edge of the rod were recorded (= total time). The smaller the rod diameter, the harder the task. The clinical score was evaluated twice a week to determine overall survival.
The orientation, travel and total times during the static rods test were higher in SOD1G93A mice compared with WT mice from 16 weeks old until disease end-stage (p<0.001). A dose-dependent improvement of motor performances was observed in SOD1 mice treated with NX210c. More particularly, the peptide at 10 mg/kg reduced ALS-induced increased orientation and travel times from 16 weeks old (WT: 1.3s and 3.2s, vehicle SOD1: 24.5s and 26.6s and 5.4s, NX210c SOD1: 2.6s and 4.8s for orientation and travel times, respectively; p<0.01) until disease end-stage on the largest diameter rod. Although no effect of NX210c at the lowest doses (i.e., 2.5 and 5 mg/kg) was observed on the overall survival of SOD1G93A mice (p>0.05), the median survival of SOD1 mice treated with NX210c at 10 mg/kg was increased by 11 days compared with that of vehicle-treated SOD1 mice (vehicle SOD1: 143d, NX210c SOD1: 154d, p<0.01).
Overall, NX210c is a new promising drug candidate and its solid preclinical package supports the clinical development of NX210c in ALS patients.