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Research Publications

State-of-the-art 2023 on gene therapy for phenylketonuria. Martinez M, Harding CO, Schwank G, Thöny B. J Inherit Metab Dis. 2024 Jan;47(1):80-92. doi: 10.1002/jimd.12651. Epub 2023 Aug 3. PMID: 37401651; PMCID: PMC10764640

Phenylketonuria (PKU) is a genetic metabolic disorder that increases the body's levels of the amino acid phenylalanine, which can build up to harmful levels if left untreated. Patients with PKU are treated with dietary therapy. However, these dietary restrictions are complicated and often difficult to follow, highlighting the need for new therapies and ultimately a cure.

In this review paper, researchers summarize, compare, and evaluate state-of-the-art gene therapy approaches for PKU. Methods include recombinant viral and non-viral vector delivery; gene addition; genome, gene, or base editing; and gene insertion or replacement. A list of current and planned clinical trials for PKU gene therapy is also included.

Authors note that this review can help advance scientific understanding and efficacy testing, paving the way for safe and efficient therapies for patients with PKU.

Phenylketonuria. van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Nat Rev Dis Primers. 2021 May 20;7(1):36. doi: 10.1038/s41572-021-00267-0.

Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments.

Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth. Manzoni F, Salvatici E, Burlina A, Andrews A, Pasquali M, Longo N. Mol Genet Metab. 2020 Dec;131(4):380-389. doi: 10.1016/j.ymgme.2020.11.004. Epub 2020 Nov 18. PMID: 33234470; PMCID: PMC7749858.

Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 (tetrahydrobiopterin) deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition.

Prospects for Cell-Directed Curative Therapy of Phenylketonuria (PKU). Harding CO. Mol Front J. 2019 Dec;3(2):110-121. doi: 10.1142/s2529732519400145. Epub 2019 Dec 12. PMID: 32524084; PMCID: PMC7286632.

This review discusses the potential for and the limitations of permanently curative cell-directed treatment of PKU (phenylketonuria, also known as phenylalanine hydroxylase (PAH) deficiency), including liver-directed gene therapy and gene editing, if initiated during early infancy.