SUMMARY
Tufts University investigator, Michelle Jacob, and Broad Institute’s Florence Wagner, have shown significant improvements in symptoms of CTNNB1 neurodevelopmental disorder in a heterozygous mouse model using a novel small molecule targeting β-catenin signaling.
BACKGROUND
The CTNNB1 mutation is an extremely rare genetic neurodevelopmental disorder occurring in only about 1 in 50,000 births. In this syndrome, a mutation in the CTNNB1 (β-catenin) gene leads to haploinsufficiency of the protein. Symptoms of the syndrome include altered muscle tone with involuntary contractions, vision difficulties and facial abnormalities as well as behavioral issues like anxiety, aggressive behavior, attention challenges and other symptoms similar to autism spectrum disorder. There are no existing treatments for CTNNB1 syndrome, instead often a team of specialists work together to abate various symptoms.
solution
Drs. Jacob and Wagner have developed a glycogen synthase kinase (GSK3) inhibitor to regulate β-catenin levels through the β-catenin/Wnt signaling pathway. In an in vivo murine model, GSK3 α and β dual paralog inhibitor normalized β-catenin of heterozygote mice to those in wildtype controls. There was also marked improvement in learning and grip strength (Fig. 2). The GSK3 α and β dual inhibitor did not increase β-catenin levels above baseline wildtype levels, eliminating the safety risk from overexpression. Ongoing preclinical in vivo studies will help to identify the most effective small molecule inhibitor of GSK3 and define the optimal dosing.
Competitive Advantage
Clinical and preclinical trials for existing treatments to behavioral symptoms like lithium show low selectivity and brain exposure in large scale screens. The GSK3α/β inhibitor showed bioavailability and activity in the brain after intra peritoneal delivery in the murine model. The small molecule also provides a clear advantage in abating symptoms over the gold standard which includes speech and occupational therapy.
IP Status: Pending US Utility Patent (WO2023056463A1)