Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke

Chloé Dumot (1) , Chrystelle Po (2) , Lucille Capin (3) , Violaine Hubert (1) , Elodie Ong (1) , Matthieu Chourrout (4) , Radu Bolbos (5) , Camille Amaz (6) , Céline Auxenfans (3) , Emmanuelle Canet-Soulas (1) , Claire Rome (7) , Fabien Chauveau (4) , Marlène Wiart (1)

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
2 ICube - Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie
3 HCL - Hospices Civils de Lyon
4 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
5 CERMEP - imagerie du vivant - Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant
6 CIC CHU Lyon (inserm)
7 GIN - Groupe d'imagerie neurofonctionnelle

Abstract With the aim of designing a preclinical study evaluating an intracerebral cell-based therapy for stroke, an observational study was performed in the rat suture model of ischemic stroke. Objectives were threefold: (i) to characterize neurofunctional and imaging readouts in the first weeks following transient ischemic stroke, according to lesion subtype (hypothalamic, striatal, corticostriatal); (ii) to confirm that intracerebral administration does not negatively impact these readouts; and (iii) to calculate sample sizes for a future therapeutic trial using these readouts as endpoints. Our results suggested that the most relevant endpoints were side bias (staircase test) and axial diffusivity (AD) (diffusion tensor imaging). Hypothalamic-only lesions did not affect those parameters, which were close to normal. Side bias in striatal lesions reached near-normal levels within 2 weeks, while rats with corticostriatal lesions remained impaired until week 14. AD values were decreased at 4 days and increased at 5 weeks post-surgery, with a subtype gradient: hypothalamic < striatal < corticostriatal. Intracerebral administration did not impact these readouts. After sample size calculation (18-147 rats per group according to the endpoint considered), we conclude that a therapeutic trial based on both readouts would be feasible only in the framework of a multicenter trial.

Domaines: Neurosciences [q-bio.NC]; Imagerie; Ingénierie biomédicale

Chloé Dumot, Chrystelle Po, Lucille Capin, Violaine Hubert, Elodie Ong, et al.. Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke. Scientific Reports, 2022, 12, pp.4700. ⟨10.1038/s41598-022-08713-z⟩. ⟨hal-03451443v2⟩