Progress in gene therapy for hereditary Tyrosinemia Type 1

Journal article : Review

Hereditary Tyrosinemia Type-1 (HT1), an inherited error of metabolism caused by a mutation in the fumarylacetoacetate hydrolase gene, is associated with liver disease, severe morbidity, and early mortality. The use of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) has almost eradicated the acute HT1 symptoms and childhood mortality. However, patient outcomes remain unsatisfactory due to the neurocognitive effects of NTBC and the requirement for a strict low-protein diet. Gene therapy (GT) offers a potential single-dose cure for HT1, and there is now abundant preclinical data showing how a range of vector-nucleotide payload combinations could be used with curative intent, rather than continued reliance on amelioration. Unfortunately, there have been no HT1-directed clinical trials reported, and so it is unclear which promising pre-clinical approach has the greatest chance of successful translation. Here, to fill this knowledge gap, available HT1 preclinical data and available clinical trial data pertaining to liver-directed GT for other diseases are reviewed. The aim is to establish which vector-payload combination has the most potential as a one-dose HT1 cure. Analysis provides a strong case for progressing lentiviral-based approaches into clinical trials. However, other vector-payload combinations may be more scientifically and commercially viable, but these options require additional investigation.

Authors: Thomas, H; Carlisle, RC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Pharmaceutics
• Volume: 17
• Issue: 3
• Article number: 387
• Publication date: 2025-03-18
• Acceptance date: 2025-03-12
• DOI: 10.3390/pharmaceutics17030387
• EISSN: 1999-4923
• Language: English
• Keywords: gene therapy; LNP; lentivirus; tyrosinemia
• Subtype: Review