Minimal Efficacy of Nitisinone Treatment in a Novel Mouse Model of Oculocutaneous Albinism, Type 3.
Minimal Efficacy of Nitisinone Treatment in a Novel Mouse Model of Oculocutaneous Albinism, Type 3.
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DOI：
10.1167/iovs.16-20293
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发表时间：
2018-10-01
影响因子：
4.4
通讯作者：
Brooks BP
中科院分区：
文献类型：
--
作者：
Onojafe IF;Megan LH;Melch MG;Aderemi JO;Alur RP;Abu-Asab MS;Chan CC;Bernardini IM;Albert JS;Cogliati T;Adams DR;Brooks BP
口服尼替西酮可增加眼皮肤白化病（OCA）小鼠模型的皮毛和眼部色素沉着，这是由于酪氨酸酶（TYR） OCA1B的亚形态突变所致。本研究确定nitisinone是否可以改善由酪氨酸酶相关蛋白1 （Tyrp1）基因突变引起的OCA3型（OCA3）小鼠模型的眼部和/或毛皮色素沉着。对Tyrp1基因（C57BL/6J-Tyrp1 b-J/J）零等位基因纯合子的小鼠，每隔一天口服8 mg/kg尼替西酮或对照物。观察皮毛和眼部黑色素沉着的变化。电镜下定量观察眼部色素结构中成熟黑色素体的数量和大小。C57BL/6J-Tyrp1 b-J/J小鼠携带新的c.403T> a；Tyrp1的404delG突变，预计会导致Tyrp1蛋白过早截断。Nitisinone治疗导致血浆酪氨酸浓度增加约7倍，无明显毒性。治疗1个月后，未观察到毛色和眼部色素结构的变化。黑素体横截面积在眼部组织中的分布没有变化。nitisinone治疗组与对照组RPE/脉络膜色素黑素体数量无显著差异。然而，虹膜中色素黑素体的数量有显著差异。口服尼替西酮治疗小鼠OCA3模型对黑色素生成没有良好的临床效果，对虹膜基质中黑色素素体的数量影响最小。因此，用尼替西酮治疗OCA3患者不太可能有疗效。
Oral nitisinone has been shown to increase fur and ocular pigmentation in a mouse model of oculocutaneous albinism (OCA) due to hypomorphic mutations in tyrosinase (TYR), OCA1B. This study determines if nitisinone can improve ocular and/or fur pigmentation in a mouse model of OCA type 3 (OCA3), caused by mutation of the tyrosinase-related protein 1 (Tyrp1) gene. Mice homozygous for a null allele in the Tyrp1 gene (C57BL/6J-Tyrp1 b-J/J) were treated with 8 mg/kg nitisinone or vehicle every other day by oral gavage. Changes in fur and ocular melanin pigmentation were monitored. Mature ocular melanosome number and size were quantified in pigmented ocular structures by electron microscopy. C57BL/6J-Tyrp1 b-J/J mice carry a novel c.403T>A; 404delG mutation in Tyrp1, predicted to result in premature truncation of the TYRP1 protein. Nitisinone treatment resulted in an approximately 7-fold increase in plasma tyrosine concentrations without overt toxicity. After 1 month of treatment, no change in the color of fur or pigmented ocular structures was observed. The distribution of melanosome cross-sectional area was unchanged in ocular tissues. There was no significant difference in the number of pigmented melanosomes in the RPE/choroid of nitisinone-treated and control groups. However, there was a significant difference in the number of pigmented melanosomes in the iris. Treatment of a mouse model of OCA3 with oral nitisinone did not have a favorable clinical effect on melanin production and minimally affected the number of pigmented melanosomes in the iris stroma. As such, treatment of OCA3 patients with nitisinone is unlikely to be therapeutic.
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影响因子：
3.5
作者：
Mondal, M.;Sengupta, M.;Ray, K.
通讯作者：
Ray, K.
DOI：
10.1073/pnas.85.12.4392
发表时间：
1988-06-01
影响因子：
11.1
作者：
JACKSON, IJ
通讯作者：
JACKSON, IJ
影响因子：
3.7
作者：
通讯作者：
--
影响因子：
11.4
作者：
KOBAYASHI, T;URABE, K;HEARING, VJ
通讯作者：
HEARING, VJ
影响因子：
30.8
作者：
DURHAMPIERRE, D;GARDNER, JM;BRILLIANT, MH
通讯作者：
BRILLIANT, MH