TIMELESS

One of the rare diseases throughout the world is Glycogen Storage Disease which appears due to problems in glycogen metabolism. Among various subtypes of GSD, GSD Type 1a is the most abundant one of GSD Type 1, seen in approximately 80%, caused by different kinds of mutations in glucose-6-phosphatase (G6PC) gene in human chromosome 17q21. G6PC gene encodes for glucose-6-phosphatase (G6Pase) protein, which cleaves glucose-6-phosphate into glucose and inorganic phosphate (Pi), and GSD Type 1a patients fail to breakdown glucose-6-phosphate due to several mutations in G6PC gene. In our study, we aim to create new therapeutic approaches for GSD 1a. We collected mutation data of 57 GSD Type 1a patients from Turkey from Intergen Genetic and Rare Disease Diagnosis Research and Application Center. According to the data, 16 types of mutations were observed in G6PC gene. Allele frequencies of these mutations are calculated as 59% for R83C/H, 11% for W160*, 7% for G270V and 28% for others which have less frequency. Up to now, tertiary protein structure of G6Pase has not been structured yet. To understand the possible impacts of these mutations, we statistically obtained possible tertiary structure predictions of G6Pase by running 5 different tools. At the end of the study, we suggest two effective and promising therapeutic methods for GSD 1a, Prime Editing for R83C/H mutations, and mRNA delivery, for other mutations, in addition to a promising, commercially available drug suggestion for patients with W160*, W86* and S15* mutations, although the drug belongs to another disease. These gene therapy systems will be delivered in hepatocyte-targeting lipid nanoparticles (LNP).