Carlos PARRAS - Pharmacogenomic screening identifies and repurposes leucovorin - bioactive form of folate - for brain repair in myelin pathologies

Oligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. I will present a pharmacogenomic approach identifying compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore, https://oligoscore.icm-institute.org) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs.
Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identified FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin de bris clearance. These findings support the repurposing of leucovorin for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS.
A paper describing our recently published study can be found at https://www.nature.com/articles/s41467-024-54003-9 and during my talk I will mentioning our current results in aging mice and human brain models.