TRANSlating BIOmarkers for Reduced DYRK1A OveractivitY in Down syndrome Along Lifetime, from animal models to human. – TRANSBIOROYAL

Down syndrome (DS) is the most common form of intellectual disabilities in the world, caused by trisomy of human chromosome 21. DS still shows a high prevalence with a strong socio-economic impact on both families and society and constitute a major unsatisfied medical need.
Among the few key driver genes, the dual-specific, tyrosine-phosphorylation-regulated kinase (DYRK1A) is a strong player whose overdosage is responsible for several cognitive defects in DS mouse models. Importantly several cognitive rescues were achieved by inhibitors targeting the DYRK1A kinase overactivity, including Leucettine L41. A new generation of DYRK1A inhibitors have been optimized with the drug candidate, Leucettinib-21 (LCTB-21) able to correct cognition in DS models. LCTB-21 has been selected to enter in regulatory preclinical phase in 2022, and phase 1 clinical trial early 2023.
Clinical evaluation of intellectual disabilities is currently done on a battery of cognitive tests. However, there is no clear consensus on their value and translatability, nor validity across age ranges and populations. A few other DYRK1A biomarkers are available to monitor the action of the drug on the kinase activity but are limited. This proposal aims at defining specific molecular and imaging biomarkers, translatable across species, to detect the engagement of the DYRK1A kinase target following oral administration of LCTB-21. It will also support the proof of principle and be a key tool to accompany the clinical evaluation of the drug candidate in parallel to cognitionand behavior. To achieve this goal, we have designed 3 tasks: (1) Select biomarkers for target engagement using DS mouse models treated with LCTB-21; (2) Challenge the selected biomarkers in a full DS rat models treated with LCTB-21 at different ages; (3) Validate the translation of selected DS biomarkers to human. Improving cognition in DS will improve the autonomy and ability of people to integrate society.