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JIMD Rep. 2015;24:45-50. doi: 10.1007/8904_2015_437. Epub 2015 May 5.

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice.

Author information

1
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.
2
Developmental Immunology, Paediatrics, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
3
School of Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Buildings, Byrom Street, Liverpool, L3 3AF, UK.
4
Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, 1-3 Brownlow Street, Liverpool, L69 3GL, UK.
5
Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK.
6
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK. jag1@liverpool.ac.uk.

Abstract

Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient.

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