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Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice.

Keenan, CM and Preston, AJ and Sutherland, H and Wilson, PJ and Psarelli, EE and Cox, TF and Ranganath, LR and Jarvis, JC and Gallagher, JA (2015) Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice. JIMD Reports, 24. pp. 45-50. ISSN 2192-8304

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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.

Item Type: Article
Additional Information: The final publication is available at Springer via http://dx.doi.org/10.1007/8904_2015_437
Subjects: R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions: Sport & Exercise Sciences
Publisher: SPRINGER
Related URLs:
Date Deposited: 28 Oct 2015 11:11
Last Modified: 05 May 2016 23:50
DOI or Identification number: 10.1007/8904_2015_437
URI: http://researchonline.ljmu.ac.uk/id/eprint/1424

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