Introduction

Therapeutic treatment of chromatinopathies, i.e. genetic dis-orders characterized by mutated genes encoding for chromatin regulators, including Kabuki Syn-drome (KS), Kabuki Syndrome 2 (KS 2), Charge Syn-drome (CS), Rubinstein-Taybi syndrome (RT) and Cornelia de Lange syndrome (CdL).

Technical features

The development of a disease model system for Kabuki syndrome by introducing a truncating mutation, the mutation of the KMT2D gene proved to be sufficient to reduce the biological structure of the MLL4 protein, which causes an altered organization of the chromatin and affects the structural properties and core mechanics. These alterations affect the ability of the affected cells to adequately respond to mechanical stimuli.
The invention consists in targeting of the ATR protein with specific drugs to re-establish the adequate mechanical properties of the cells, with a consequent recovery of the phenotype involved. In particular, it has been observed that the ATR inhibitor known as VX-970 is effective in blocking the activity of ATR at the level of the nuclear mechanics of the cells affected by mutations in the KMT2D gene, which causes the Kabuki syndrome.

Possible Applications

• Therapeutic treatment of Kabuki syndrome patients;
• Therapeutic treatment of patients affected by other chromatinopathies.

Advantages

• It is the only existing therapeutic option to treat Kabuki syndrome patients;
• The drug VX-970 represents a feasible therapeutic option to alleviate the suffering of the patients affected by Kabuki syndrome;
• ATR or CHK1 inhibitors can be applied to treat Kabuki syndrome patients;
• The identified therapeutic principle can be applied to treat patients with other similar chromatinopathies.