Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice
Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice
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DOI：
10.1007/8904_2015_437
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发表时间：
2015-01-01
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影响因子：
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通讯作者：
Gallagher, James A.
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作者：
Keenan, Craig M.;Preston, Andrew J.;Gallagher, James A.
尿白蛋白（AKU）是一种罕见的常染色体隐性遗传疾病，由尿黑酸1，2双加氧酶（HGD）缺乏引起，HGD是一种参与苯丙氨酸和酪氨酸催化的酶。HGD功能的丧失阻止尿黑酸（HGA）的代谢，导致血浆HGA和尿排泄水平增加。过量的HGA沉积在胶原组织中，随后主要在负荷关节的软骨中进行聚合，这一过程称为褐变。这导致了早期发作的破坏性骨关节病，目前还没有有效的治疗方法。我们最近在AKU小鼠模型中描述了褐变的自然史，表明褐变色素的沉积在生命的早期就开始了，并随着年龄的增长而积累。使用这个模型，我们能够证明用尼替西酮（一种潜在的AKU治疗方法）终生治疗能够完全防止褐变色素的沉积。然而，尽管尼替西酮已被证明可以抑制褐变沉积，但它是否也可以促进现有色素的去除尚未被研究。我们在这里描述的是，中年管理nitisinone的AKU小鼠逮捕胫股关节中的褐变色素的进一步沉积，但不会导致清除现有的色素。我们还证明了血浆HGA对尼替西酮的剂量依赖性反应，突出了其用于个性化药物的功效，其中剂量可以根据个体AKU患者进行定制。
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.