Prime Medicine touts preclinical success for next-gen gene editing approach

2023-10-27

基因疗法

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 edits

The 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 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."

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