Prime Medicine, Inc. reported new preclinical data demonstrating the ability of liver-targeted Prime Editors to efficiently and precisely correct one of the most prevalent disease-causing mutations of glycogen storage disease 1b (GSD1b) in non-human primates (NHP) and mouse models. The data were presented at the European Society of Gene and Cell Therapy (ESGCT) 2023 Congress in Brussels, Belgium. GSD1b is a rare, serious progressive disease that causes impaired glycogen metabolism and affects approximately 1,500 patients.

It results from mutations in the glucose-6-phosphate transporter (G6PT), which is encoded by the gene SLC37A4. Deficiencies in this transporter result in hypoglycemia, or low blood glucose levels, which can be fatal if patients do not adhere to a strict dietary regimen, including consuming slow-release glucose and overnight feeding. P.L348fs and p.G339C mutations are known to be the most prevalent disease-causing mutations and are found in approximately 46-52% of the GSD1b patient population.

According to scientific literature and Prime Medicine research, correcting SLC37A4 gene mutations in fewer than 10% of liver cells may be sufficient to reverse many manifestations of this disease. To address the underlying genetic cause of GSD1b, Prime Medicine is advancing Prime Editors that are delivered to the liver by single intravenous infusion and designed to enable a precise correction of the disease-causing mutations, restoring G6PT protein expression and glucose homeostasis. The Prime Editors are composed of a Prime Editor guide RNA (pegRNA) targeting the respective mutations, a nick-guide RNA (ngRNA) and a messenger RNA (mRNA) packaged in Prime?s universal lipid nanoparticle (LNP) formulation that includes a ligand targeting the LNP to hepatocytes.

Through high-throughput screening and subsequent optimization, Prime researchers identified pegRNAs that precisely corrected the p.L348fs and p.G339C mutations in liver cells, which were then evaluated in vitro, demonstrating average editing of 77% and 37%, respectively. In today?s presentation at ESGCT, Prime Medicine highlighted data from in vivo rodent and NHP studies with its Prime Editor targeting the p.L348fs mutation. Key findings from the studies showed: Up to 50% whole liver precise editing of p.L348 in NHPs at day 14 without significant on-target unintended edits.

Up to 83% of the key target cells, liver hepatocytes, were estimated to have both alleles precisely edited by this single LNP administration. Up to 56% whole liver precise correction of the p.L348fs mutation in a GSD1b humanized mouse model with on-target unintended editing of less than 0.2% across dose levels evaluated. Prime Editing of up to 44% led to restored levels of G6PT protein expression of up to 46%, with the extent of correction directly correlating with the extent of G6PT protein restoration in the humanized mouse model.

Redosing of the universal LNP in non-naïve animals was tolerated similarly to naïve animals with no infusion reactions, no body weight changes, and transient, modest liver function changes that resolved by day 7; minimal transient cytokine abnormalities were observed. No detectable off-target edits were observed in patient-derived induced pluripotent stem cells (iPSCs) following a comprehensive off-target screening analysis, consistent with what has been observed to date across Prime Medicine?s extensive off-target analyses for each of its programs. These findings provide important proof-of-concept for Prime Medicine?s LNP liver-targeted delivery approach, and support the further advancement of the Company?s Prime Editors targeting the p.L348fs and p.G339C mutations in GSD1b, as well as its additional liver-targeted programs.