​NO PHARMACOLOGICAL TREATMENT FOR HIE

Neonatal HIE is a serious brain injury resulting from a significant reduction in blood flow and oxygen to the brain at birth. Responsible for almost one million deaths a year (24% of all newborn deaths worldwide), neonatal HIE is a major medical concern. Its prevalence in 2019 is between 11,000 and 88,000 cases in developed countries and 2,444,000 in developing countries. In addition to mortality, HIE can cause long-term neurological deficits, severe learning and intellectual deficits, and cognitive and behavioural development disorders. Once the diagnosis has been made, the newborn with HIE must be rapidly managed. Therapeutic hypothermia is currently the only approved therapy, but it can only be used to treat full-term newborns and is only partially protective. To date, therefore, there is no pharmacological treatment offering protection against these lesions, which result from too little blood or oxygen being supplied to the brain, and are associated with dysfunction of cerebral endothelial cells and altered neuronal activity.

HOPE WITH PURINE DERIVATIVES

For several years, Aloïse Mabondzo's laboratory has been investigating the pharmacological properties of purine derivatives that could be effective in the treatment of certain brain lesions. In an article published in the journal Neurotherapeutics, the researchers continued the development of a drug candidate, a druggable purine derivative, BRT_002, initially named BRT_001 (see Joliot news). This molecule is a valine ester with good cerebral bioavailability and anti-inflammatory and neurovascular protective properties. In a rodent model of brain damage linked to a neonatal hypoxic-ischemic event (HI), the researchers demonstrated BRT_002's ability to reduce lesions, restore long-term cognitive impairment, improve mitochondrial and synaptic functions, induce neurogenesis and reduce neurovascular inflammation. A global proteomic analysis of lesional and non-lesional areas, combined with the identification of biological variables using bioinformatics, enabled to identify three key biomarkers in the pharmacodynamics of BRT_002: i) agrin, a protein present in large quantities at the synapses of neuromuscular junctions, involved in the integrity of the blood-brain barrier; ii) zyxin, a cytoskeletal protein involved in angiogenesis; iii) synaptotagmin-5, interacting with proteins involved in mitochondrial respiration. The study of protein-protein interactions by Protein-Ligation Assay revealed that these three proteins interact and that these molecular interactions very probably contribute to the pharmacological action of BRT_002.

The identification of biomarkers likely to be involved in the pharmacological action of BRT_002, combined with the preclinical data obtained in an animal model of HI, provide a solid basis for the development of this new purine derivative to treat HIE in neonates.

Contact Joliot : Aloïse Mabondzo (aloise.mabondzo@cea.fr)​