Transient Prime Editor Expression Treats Phenylketonuria in Mice

A team of researchers in Switzerland, Canada and the United States recently shared the results of a study that led to successful treatment of phenylketonuria in mice using a transient prime editor.

In contrast to several other proof-of-concept studies demonstrating in vivo prime editing, where the prime editor is typically delivered on a viral vector, the team, led by Gerald Schwank at the University of Zurich, chose to deliver the pegRNA using self-complementary adeno-associated viral (scAAV) vectors and the prime editor (PE) using nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNPs). This approach resulted in transient expression of the PE for 48h, which is arguably more attractive than viral-based PE delivery methods that lead to prolonged PE expression after the desired edit has been made.

When applied to a mouse model of phenylketonuria (PKU), the team observed 4.3% gene correction at the intended locus, and specifically in the liver, using an AAV dose of 2.5×10¹³ vg/kg and three doses of 2 mg/kg mRNA-LNP. Encouragingly, the level of editing achieved was sufficient to reduce blood L-phenylalanine (Phe) levels from over 1500 µmol/l to below the therapeutic threshold of 600 µmol/l.

Read the manuscript on the preprint server bioRxiv here.

doi.org/10.1101/2024.01.22.575834