CE17 - Recherche translationnelle en santé

Two FDA-approved drugs promoting oligodendrogenesis in preterm birth brain injury – NeoReGen

Submission summary

Preterm-birth brain injury (PBI) is a public health concern, with many surviving children developing cognitive and neuropsychiatric deficits implying a strong social and economic burden. The developmental period around birth is a time of active generation of oligodendrocytes, myelination, and axonal reorganization that if strongly perturbed in many preterm-born children. Through a pharmacogenomics analysis based on the generation and expert curation of transcriptomic datasets, we identified novel small bioactive molecules fostering oligodendrogenesis by acting on their proliferation or maturation. We demonstrated their pro-oligodendrogenic activity in mice both in vitro (neural progenitor cell- and primary oligodendroglial progenitor cell-cultures), ex-vivo (cerebellar slice cultures), and in vivo (adult focally demyelinated brain). In this new project, we will assess whether the distinct transcriptional changes induced by these two FDA-approved small molecules may impact other lineages than oligodendroglia, and whether they may prove to have distinct efficiencies depending of pathological context (i.e. nature of the pathology), or species (mouse vs. human). To achieve this, we will: first, explore potential side effects in endogenous neural stem cells and their long-term neurogenic capacity, in an in vivo hypoxia model; second, complete this preclinical investigation with two clinically relevant models of PBI, both resulting in dysmyelination but through distinct mechanisms involving inflammation or metabolic perturbation; and third, we will provide the proof of concept that the drugs have similar activities in human cells, using 3D cultures (i.e. organoids) favoring human iPSCs differentiation into oligodendroglia and myelin formation. The achievement of these goals will pave the way towards repurposing two novel FDA-approved small molecules for the treatment of PBI, and potentially for demyelinating diseases such as multiple sclerosis.

Project coordinator

Monsieur Carlos Parras (Institut du Cerveau et de la Moelle épinière)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

NeuroDider Institut national de la sante et de la recherche medicale
(SBRI) Institut national de la sante et de la recherche medicale
ICM Institut du Cerveau et de la Moelle épinière

Help of the ANR 564,073 euros
Beginning and duration of the scientific project: September 2022 - 48 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter