Glycogen Storage Disease IB

The prime editors were targeted to and designed to edit hepatocytes, which make up roughly 60% of the cells in the liver. Prime Medicine’s prime editors have corrected a gene mutation in primates that causes a rare liver disease, a step toward taking the tech to humans. In an Oct. 27 presentation at the annual European Society of Cell & Gene Therapy Congress in Brussels, the company showed that a single dose of its therapy could repair the gene associated with glycogen storage disease 1b in up to 83% of target cells in the livers of primates. An estimated 10% correction is required for therapeutic benefit in humans, according to the company. “[We] are highly encouraged by the efficient and precise corrections we have observed across in vitro evaluations, in vivo rodent studies and now, NHP studies,” Jeremy Duffield, M.D., Ph.D., Chief Scientific Officer at Prime Medicine, said in a press release. “Importantly, we continue to observe minimal to no detectable off-target edits with our Prime Editors, providing further confidence in the precision of this technology.” A primer on prime editing: The tech is another way to edit genes, but with more functionality than CRISPR. If CRISPR is like scissors that snip out mutated gene sequences, prime editors are like a keyboard’s search-and-replace functionality, using what’s known as Prime Editing guide RNAs, or pegRNAs, to find a mutated sequence and alter it, thereby correcting the pathology that stems from it. Each of the primates in the new study received a single dose of prime editors delivered in Prime Medicine’s universal lipid nanoparticle. The therapy was designed to repair the p.L348 mutation in the gene SLC37A4, one of the causes of glycogen storage disease 1b. Roughly half of the primates had never received gene therapy before, while the other half had previously been treated with a universal lipid nanoparticle to target a different gene. In an email to Fierce Biotech Research, the company said they could not comment on the previously edited gene, though they noted that if the prior therapy had any impact on the new one, it would have decreased editing efficacy.   The prime editors were targeted to and designed to edit hepatocytes, which make up 60% of the cells in the liver. In the primate with the best response, the editors corrected the mutation in an estimated 50% of all liver cells and 83% of hepatocytes, Prime’s presentation showed. In the other animals, editing was between 20% and 40% of all liver cells. The researchers found few off-target edits in the cells, and while they noted some transient moderate changes to liver function tests and minimal cytokine abnormalities, there were no lasting or serious side effects. The animals that had previously received a different gene therapy tolerated the drug no differently than those who were being treated for the first time. In an email to FBR, the team said that although they will have to see clinical data before they can determine the clinical benefit in humans, “high-level prime editing in NHP is likely to support that we can achieve high-level editing in humans,” they wrote. They declined to comment on a timeline for clinical testing. Prime is studying the use of prime editors in other conditions, too. The company reported in May 2023 that they had corrected a mutation that leads to chronic granulomatous disease in human stem cells that were engrafted into mice, with an efficacy rate of 90%.

Prime Medicine, a biotech company developing a new class of gene editors that promises to make nearly any change to any gene, said the first tests of its technology in animals were successful, paving the way to human studies. One of the company’s experimental treatments is for a rare liver condition called glycogen storage disease Ib (GSDIb). When delivered via lipid nanoparticle infusion, the in vivo therapy edited up to 50% of liver cells in monkeys and up to 56% of liver cells in mice — far more than the estimated 10% editing needed for a therapeutic effect. You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.

Prime Medicine on Friday presented data at the European Society of Gene and Cell Therapy (ESGCT) conference demonstrating the ability to "efficiently and precisely" correct disease-causing mutations in preclinical models of glycogen storage disease 1b (GSD1b) using its liver-targeted "prime editors." Chief scientific officer Jeremy Duffield said "these data are the first prime-editing data in NHPs (non-human primates) and provide further proof-of-concept for our prime-editing approach to potentially address a wide range of diseases."GSD1b is caused by alterations in the glucose-6-phosphate transporter (G6PT) enzyme, which is encoded by the SLC37A4 gene. The p.L348fs and p.G339C mutations are recognised as the most commonly occurring disease-causing mutations, present in roughly half of individuals with the disease. Prime Medicine says its work suggests that correcting SLC37A4 gene mutations in fewer than 10% of liver cells may be enough to reverse many manifestations of GSD1b.'Minimal' off-target editsThe company designed prime editors against the p.L348fs and p.G339C mutations. The platform consists of a prime editor guide RNA (pegRNA) targeting the mutations, a nick-guide RNA (ngRNA) and mRNA packaged in a lipid nanoparticle (LNP) formulation that includes a ligand targeting the LNP to hepatocytes. They have corrected p.L348fs and p.G339C mutations in vitro with 77% and 37% editing efficiency, respectively.According to early in vivo data presented at the ESGCT conference, up to 83% of hepatocytes in NHPs had both alleles precisely edited following a single intravenous infusion of prime editors, and up to 56% whole-liver editing was observed in a GSD1b mouse model, with "minimal" off-target edits. Further, achieving prime editing of up to 44% resulted in the restoration of G6PT protein expression levels of up to 46%. The company noted that the degree of correction showed a direct correlation with the extent of G6PT protein recovery in the mouse model."We…are highly encouraged by the efficient and precise corrections we have observed across in vitro evaluations, in vivo rodent studies and now, NHP studies," Duffield said, adding "importantly, we continue to observe minimal to no detectable off-target edits with our prime editors, providing further confidence in the precision of this technology." The start-up launched in 2021 with $315 million in hand to advance its prime-editing technology. Meanwhile, Tessera Therapeutics - which is developing what it refers to as Gene Writing technology that can "enable both writing and rewriting of the genome" – reported in May that its platform was able to correct pathogenic mutations responsible for phenylketonuria (PKU), alpha-1 antitrypsin deficiency and sickle-cell disease. At the time, the company said that NHPs treated with its gene-editing technology showed in vivo rewriting efficiencies at the gene associated with PKU of up to 45% in the liver, "well above the 10% curative threshold."