Identification of new therapeutic agents for the treatment of Glycogenosis type 2 due to the common splicing mutation c.-32-13T>G

In order for genes to exert their effects DNA must be copied in a molecule called pre-mRNA. In turn, this pre-mRNA molecule must be correctly processed in mRNA before it can be translated into a protein. In particular, the pre-mRNA sequences used to direct the production of this protein (exons) must be joined together whilst the unnecessary parts (introns) must be removed. The process responsible for this joining is called pre-mRNA splicing. Mistakes in this process are often the cause of disease in humans. In this project, we will analyze a common splicing mutation c.-32-13T>G that is present in most patients affected by Glycogenosis Type 2 (G2). G2 is one of the most prevalent (1: 40,000) autosomal recessive inherited lysosomal storage disorder due to the deficiency of acid alpha glucosidase (GAA) that results in impaired glycogen degradation and accumulation within the lysosomes. In this project we will use our previously obtained knowledge on the molecular mechanisms of this mutation and use this information to set up novel mRNA-splicing based techniques aimed at restoring normal splicing regulation in human patients. Ideally, our approach will result in obtaining novel therapeutic effectors that could be used to increase the efficacy of existing treatments that currently suffer from several limitations.