The contribution of mouse models in the rare disease alkaptonuria

Q3 Pharmacology, Toxicology and Pharmaceutics
Juliette H. Hughes , George Bou-Gharios , Lakshminarayan R. Ranganath , James A. Gallagher
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Abstract

Alkaptonuria is an ultra-rare autosomal recessive disorder of tyrosine metabolism, whereby the homogentisate 1,2-dioxygenase (HGD) enzyme is deficient, causing an elevation of its substrate homogentisic acid (HGA). Overtime, elevated HGA causes connective tissue ochronosis, leading to a severe and early onset osteoarthropathy. The use of HGD deficient mouse models in this metabolic bone disease have provided the opportunity to investigate AKU pathophysiology and potential treatments. An ENU mutagenesis AKU mouse model (BALB/c Hgd−/−) provided the means to explore the onset of pigmentation in cartilage and treatment of AKU with nitisinone, an inhibitor of the upstream enzyme forming HGA. This work provided evidence that nitisinone could not only lower circulating HGA, but could also prevent ochronosis and halt disease progression, leading to its off-label use at the National Alkaptonuria Centre (Liverpool, UK) and its subsequent testing in human clinical trials (DevelopAKUre). Recently, a new targeted AKU mouse model (Hgd tm1a−/−, C57BL/6) has been established, offering a LacZ reporter gene for localising gene expression and LoxP and FRT sites that enabled generation of an inducible and liver-specific HGD knockout model (Hgd tm1d MxCre+/−). This conditional model determined the importance of the liver as a target organ for future gene/enzyme replacement therapies in AKU. The contribution of AKU mouse models has clearly accelerated the treatment and knowledge of this rare disease, and will continue to be used.

小鼠模型在罕见病尿酸尿中的作用
Alkaptonuria是一种罕见的常染色体隐性遗传病的酪氨酸代谢,其中均质1,2-双加氧酶(HGD)缺乏,导致其底物均质酸(HGA)升高。随着时间的推移,升高的HGA引起结缔组织衰老,导致严重和早发性骨关节病。在这种代谢性骨病中使用HGD缺陷小鼠模型为研究AKU的病理生理和潜在治疗提供了机会。ENU诱变AKU小鼠模型(BALB/c Hgd - / -)为探索软骨色素沉着的发生和nitisinone(一种上游酶形成HGA的抑制剂)治疗AKU提供了手段。这项工作提供的证据表明,nitisinone不仅可以降低循环HGA,而且还可以预防衰老和阻止疾病进展,导致其在国家Alkaptonuria中心(Liverpool, UK)的标签外使用,并随后在人体临床试验中进行测试(DevelopAKUre)。最近,建立了一种新的靶向AKU小鼠模型(Hgd tm1a−/−,C57BL/6),该模型提供了LacZ报告基因,用于定位基因表达和LoxP和FRT位点,从而产生了可诱导的肝脏特异性Hgd敲除模型(Hgd tm1d MxCre+/−)。这个条件模型确定了肝脏作为未来AKU基因/酶替代治疗靶器官的重要性。AKU小鼠模型的贡献显然加速了对这种罕见疾病的治疗和认识,并将继续使用。
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来源期刊
Drug Discovery Today: Disease Models
Drug Discovery Today: Disease Models Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
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期刊介绍: Drug Discovery Today: Disease Models discusses the non-human experimental models through which inference is drawn regarding the molecular aetiology and pathogenesis of human disease. It provides critical analysis and evaluation of which models can genuinely inform the research community about the direct process of human disease, those which may have value in basic toxicology, and those which are simply designed for effective expression and raw characterisation.
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