The pre-clinical phase of development for非酒精性脂肪肝（纳什）药物面临着许多挑战。生物制药公司对啮齿动物模型有几个选择，但在决定最佳方法之前，它们必须体重定制与速度等因素。
Some of the challenges include:
- 饮食：领域没有普遍的智慧，表明一种感应饮食优于另一个。
- Duration of disease induction: Depending on the type of diet, it will take 6 to 9 months for models to exhibit NASH-like features.
- Translation: Novel biomarkers used in human clinical trials need further validation in rodent models.
Despite these issues, companies can reduce their risk by using short-term models for early screening. As the models move through three stages of the disease, an array of biomarkers can be measured to assess factors such as fat accumulation and fibrosis.
定制的疾病米odels
用于临床前纳什研究的诱导饮食补充了高脂肪。富含饱和脂肪酸，反式脂肪酸，果糖或蔗糖等营养素的饮食，甚至没有其他营养素如甲硫氨酸和胆碱，可能会破坏不同的途径以产生肿瘤。此时，不同的给药时间和饮食产生不同的结果。
As companies begin pre-clinical trials, they may have to choose between customization and speed. Some contract research organizations (CROs) provide models that have already been induced, which reduces the waiting period. However, the client cannot specify the exact induction diet.
Alternatively, companies can request that a CRO custom-make the models with a certain diet. This approach, while more predictable, requires more time. But early screening data can be obtained through short-term models in which agents such as carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN) are used to induce liver fibrosis. These models can help companies evaluate whether their compound has anti-fibrotic features.
Three phases of disease
The disease created by diet induction progresses through three distinct phases:
(1) Accumulation of fat (non-alcoholic fatty liver disease,NAFLD）。通常，在显微镜下检查肝脏的一部分以确认疾病状态。生物化学测定可以表明甘油三酯水平。使用MRI的脂质谱也可以提供关于脂质累积的数据，但这种技术是专业化的，并且可能是成本持久的。
(2) NAFLD progresses to NASH. Typical biomarkers at this stage include elevated liver enzymes such as alanine aminotransferase (ALT). The marker cytokeratin-18 (CK-18), which is linked with necrosis and apoptosis in the liver, is sensitive and specific for increased inflammation in livers previously filled with fat.
(3) Fibrosis. When normal liver cells die, the organ responds by producing fibrotic tissue. A fibrosis index integrates levels of hyaluronic acid, tissue inhibitor of metalloproteinase 1 (TIMP-1) and amino-terminal propeptide of type III procollagen (PIIINP). A pathologist may also examine a section of the liver under a microscope to assess the amount of fibrosis.
随着疾病的进展，由于炎症和纤维化改变，肝脏循环压力增加。小血管中的血流被堵塞，并且门槛压力升高。因此，静脉压力测量可以作为另一种疾病标志物。
NAFLD在人类中慢慢发展，通常花几十年来发展和进步。然而，啮齿动物的寿命非常短，并且疾病进展可能只需要在实验系统中几周或数月。虽然啮齿动物模型的进展速率比人类更快，但饮食诱导的大鼠中的许多典型的组织学特征在具有非酒精性肝病中的典型组织学特征非常类似于人类中所见的大鼠。
从临床前到临床
这些生物标志物中的许多诸如CK-18和透明质酸，可以与人类临床试验中的终点对齐。例如，可以测试患者血液样品的CK-18和纤维化标记物。也可以进行肝脏和门栅压力测量的MRI扫描。
With strong experience spanning pre-clinical to post-development,Covancecan provide the expertise needed to navigate thechallenging early phase of NASH development.
