Molecular approaches for potential therapies in Ataxia Telangiectasia cellular model

Ataxia Telangiectasia is a very rare severe pleiotropic neurodegenerative disease, with no currently available cure. Beneficial effects on neurologic features in AT patients have been described with dexamethasone (dex) administration by autologous erythrocytes EryDex in a phase II clinical trial, leading the researchers to explore the molecular mechanisms behind the drug action. For this purpose, in the attempt to explain dex outcomes in AT cells, we reported two novel biomolecular pathways specifically induced by dex in AT cells. The first one promotes a non-epigenetic function of HDAC4 and improves autophagy progression, a usually AT compromised pathway. The second one modulates Lamin A/C dynamics and its role in gene expression regulation, contributing to clarify the positive effects of dex in AT patients. Additionally, a simulation of patients’ treatment has been performed, revealing a differential gene expression variation between WT and AT cells. Afterwards, ATM variants, originated from alternative splicing of ATM messenger and detected in vivo in the blood of AT patients treated with EryDex, were characterized in fibroblast cell lines. We were able to describe their positive role in overcoming ATM absence in AT cells, supporting their capability in partially reversing AT phenotype and supporting their potential application for gene therapy for the treatment of AT patients and/or ATM mutations.