Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice

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.

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria

“…Recently, a drug called nitisinone (2‐(2‐nitro‐4‐[trifluoromethyl]benzoyl)cyclohexane‐1,3‐dione; NTBC) that blocks 4‐hydroxyphenylpyruvic acid dioxygenase (HPPD; EC 1.13.11.27) which converts 4‐hydroxyphenylpyruvic acid (HPPA) into HGA was shown to prevent ochronosis in AKU mice, leading to a series of human clinical trials assessing nitisinone in AKU . The SONIA‐1 trial concluded that nitisinone effectively reduces HGA to a level likely to prevent ochronosis .…”

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

“…1.13.11.27), the enzyme that produces HGA, and it is currently the most effective treatment for AKU. Nitisinone reduces plasma and urine HGA concentrations (Phornphutkul et al, 2002;Introne et al, 2011;Olsson et al, 2015;Ranganath et al, 2016;Milan et al, 2017), completely arrests ochronosis in AKU mice (Preston et al, 2014;Keenan et al, 2015) and more recently was shown to slow progression of morbidity in patients attending the UK NAC (2mg nitisinone daily) (Ranganath et al, 2018). We showed previously in serum and urine that nitisinone induced an extended network of metabolic alteration within tyrosine and neighbouring pathways, including tryptophan, purine and TCA cycle (Davison et al, 2019a;Norman et al, 2019).…”

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

“…In AKU mice administration of p‐hydroxyphenylpyruvate dioxygenase (EC:1.13.11.27; HPPD) inhibitors, such as nitisinone, soon after birth resulted in failure to pigment, while a similar administration of HPPD inhibitors during the middle of the life span of the mouse, when pigmentation has already developed, prevented progression, but not reversal, of pigmentation . This suggests that HPPD inhibitors, by decreasing HGA, can modify the OP process in AKU mice.…”