LEAD PROJECT 1: PHENYLKETONURIA (PKU)

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PROJECT SUMMARY Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the gene encoding phenylalanine hydroxylase (PAH), resulting in the accumulation of phenylalanine (Phe) to neurotoxic levels. Among the five most frequently occurring pathogenic PAH variants worldwide is the c.842C>T (P281L) mutation, which is amenable to adenine base editing. The current treatment options have significant limitations—a strict low-Phe diet to which many patients find it difficult to adhere, and a daily injectable enzyme therapy with a substantial risk of anaphylaxis. Lead Project 1 will focus on a lipid nanoparticle (LNP)-based adenine base editing treatment for PKU in patients with the P281L variant, with the aim to file an IND application by the end of the five-year funding period and begin a phase 1/2 clinical trial soon afterwards.