我国成年人患肥胖症及超重已达50%人群, 而肥胖症是代谢性疾病 (如糖尿病、非酒精性脂肪肝病)、心血管疾病 (如高血压、中风、动脉粥样硬化、心机梗塞) 及一些肿瘤发生和发展的危险因素 (LANCET Diab & Endocrinol 2021;9:373-392)。昆明科灵生物科技有限公司 (KBI) 在食蟹猴建立起大规模自发性和高脂饮食诱导两类肥胖模型，伴随不同程度的上述疾病，与人类过食和高脂饮食两大成因高度契合 (见下图)。
人口老龄化时代的来临使老年疾病成为社会健康的突出问题，常见的诸如糖尿病、心脏功能衰竭（HF）、慢性肾脏疾病（CKD）、非酒精性脂肪肝炎（NASH）、血液脂质代谢异常、脏器纤维化病变、眼睛疾病、脑血管疾病以及中枢神经退行性疾病等。这些疾病正在成为创新药物研发的新领域和新热点。 昆明科灵生物科技有限公司成立12年来专注于非人灵长类临床前实验研究，已经运用老龄猴群为客户做了多种包括血液、脑脊液、脂肪、肝脏、肾脏、胰腺等组织的样品采集检测项目、老年猴子药物代谢项目、以及针对老年猴疾病模型的药理药效项目。为国内外大型药企、新药科创公司以及科研院所提供了大量研发服务，为多个创新药物进入各期临床试验以及成功上市保驾护航。 科灵公司在多年的动物资源积累和疾病模型的筛选、诱导和验证过程中，获得一个数量非常可观的老年食蟹猴群，其中20-26岁的食蟹猴就有251只。它们的这个年龄相当于我们人类的80-100岁，出现了和人类一样的各种老年性疾病（如下图所示）。这批珍贵的老龄猴资源对临床前药物研发具有非常宝贵的价值，希望它们能为老年疾病的研究以及新药开发发挥作用，也期待我们能为客户提供更优质更齐全的临床前实验服务。
视网膜病变在中老年人群中发病率极高，而现有药物治疗效果欠佳。基因疗法有望从根本上突破这一难题。但因眼球具有特殊的生理结构，常规给药途径无法直接将治疗基因递送到视网膜病灶区，且易导致产生副作用。
慢性肾病（chronic kidney disease, CKD）可导致肾功能衰竭、甚至死亡。近年来全球CKD患病率持续上升，已成为危害公共健康的主要疾病和沉重负担。糖尿病、高血压是CKD发生和发展重要的原因。
根据世卫组织发表的报告，全世界有超过10亿人患有阿尔茨海默病、多发性硬化症、癫痫、帕金森病和中风等中枢神经系统 (CNS)疾病。仅2020年，全球CNS治疗市场规模为约1162亿美元，预计从2021到2028的复合年增长率为7.4%。但目前仍缺乏治疗CNS疾病的有效疗法，全球医药行业对治疗CNS疾病新药研发的热度正在升温。CNS药物研究中，受试药物能否穿过血脑屏障到达预期CNS部位会直接影响其药效。因此脑脊髓液（CSF）对确定受试药物在CNS药代动力学研究中至关重要。非人灵长类动物疾病模型与临床研究最为接近，采集CSF对于评估受试药物在临床应用前景时具有独特的重要意义。然而，非人灵长类动物采集CSF必须在麻醉状态下，通过脊髓穿刺获得，操作技术难度极高。
Lingling Yu, Chao Wen, Xing Li, Shiqi Fang, Lichuan Yang, Tony Wang, Kaifeng Hu Abstract Quantification of endogenous and exogenous plasma glucose can help more comprehensively evaluate the glucose metabolic status. A ratio-based approach using isotope dilution liquid chromatography tandem mass spectrometry (ID LC-MS/MS) with indirect multiple reaction monitoring (MRM) of the derivative tag was developed to simultaneously quantify endo-/exogenous plasma glucose. Using diluted D-[13C6] glucose as tracer of exogenous glucose, 12C6/13C6 glucoses were first derivatized and then data were acquired in MRM mode. The metabolism of exogenous glucose can be tracked and the concentration ratio of endo/exo-genous glucose can be measured by calculating the endo-/exo-genous glucose concentrations from peak area ratio of specific daughter ions. Joint application of selective derivatization and MRM analysis not only improves the sensitivity but also minimizes the interference from the background of plasma, which warrants the accuracy and reproducibility. Good agreement between the theoretical and calculated concentration ratios was obtained with a linear correlation coefficient (R) of 0.9969 in the range of D-glucose from 0.5 to 20.0 mM, which covers the healthy and diabetic physiological scenarios. Satisfactory reproducibility was obtained by evaluation of the intra- and inter-day precisions with relative standard deviations (RSDs) less than 5.16%, and relative recoveries of 85.96 to 95.92% were obtained at low, medium, and high concentration, respectively. The method was successfully applied to simultaneous determination of the endo-/exogenous glucose concentration in plasma of non-diabetic and type II diabetic cynomolgus monkeys. Keywords Derivatization . Diabetes . Endogenous glucose . Exogenous glucose . LC-MS/MS
CONTROL ID: 2776800 PRESENTATION TYPE: Poster Only CURRENT CATEGORY: Steatosis and Steatohepatitis CURRENT DESCRIPTORS: SO1. Steatohepatitis: Experimental TITLE: Development and Characterization of High Fat Diet-induced Non-human Primate Models of Liver Diseases:Steatosis, NASH and Fibrosis AUTHORS (FIRST NAME, LAST NAME): Lichuan Yang1, Joseph Gabriel1, Zhenghua Zhu1, Feng Li1, Yuchao Zhao1, Guanzhong Wang1, Rosario Perez1, Shaodong Li1, Tony Wang1, Bob Zhang1 Oral/Poster: Institutional Author(s): (none) INSTITUTIONS (ALL): 1. Kunming Biomed International, Kunming, Yunnan, China. ABSTRACT BODY: Abstract Body: Background: Lack of translatable animal models is a major challenge for developing nonalcoholic steatohepatitis (NASH) therapies. This study aims to develop a large colony of high fat diet (HFD)-induced nonhuman primate (NHP) liver disease models to facilitate new NASH drug discovery. Methods: Over 1,500 male cynolmolgus monkeys were fed with HFD over 2-6 years. Metabolic syndrome phenotypes and diabetes progression were monitored longitudinally by body weight, IVGTT, BP and clinical chemistry. Liver steatosis was measured by ultrasound liver scan and quantitated by MRI. MRI assessment was validated by liver biopsy and hepatic triglyceride (TG). NASH was assessed by histological analysis of liver biopsy after HE staining. Liver fibrosis was evaluated by ultrasound elastography for stiffness (kPa) and biopsy after Sirius Red staining. NAFLD activity score (NAS) and fibrosis score (FS) were generated by the scale from NASH Clinical Research Network. Results: Majority of HFD-fed monkey colony developed metabolic syndrome phenotypes, as well as diabetes and diabetic complications. MRI liver fat fraction (FF) measurements performed in a representative cohort of 33 HFD-fed monkeys showed that 18 monkeys (55%) had FF >5% (cutoff value for steatosis), with average of 12.4±5.5%; while 10 normal monkeys had FF value of 2.7±0.6%. MRI FF levels correlated well with Oil Red O and HE staining of liver biopsies and hepatic TG levels (R2=0.85, p<0.05; n=12). Limited liver biopsy on monkeys (N=62) demonstrated 40 monkeys (64%) had NASH phenotype (NAS score of 4-7), including severe steatosis, moderate ballooning, and lobular inflammation. 20 of these NASH monkeys (32%) showed perisinusoidal/portal/periportal/bridge fibrosis (FS scores 1-3). Ultrasound elastography showed higher liver stiffness in NASH monkeys (kPa=4.79±1.09, n=10) compared to normal monkeys (kPa=1.14±0.25, n=10; p<0.009). 4 of 10 NASH monkeys had kPa >7.7 (cutoff value for human fibrosis). Their fibrosis stages were confirmed by liver biopsy. Conclusion: HFD-induced NHP liver disease models have been developed and characterized in a large cohort. They have similar disease progression and pathological features seen in humans. Based on limited MRI and liver biopsy data, it is estimated that 55% of monkeys on HFD diet have steatosis (>800), 64% of steatosis monkeys have NASH (>500) and 32% of NASH monkeys have fibrosis (>150). These models have potential translational values for therapeutic evaluation of anti-NASH agents. (no table selected) (No Image Selected) Co-Author Disclosure Status The following authors have completed their AASLD 2017 disclosure: Lichuan Yang: Disclosure completed | Joseph Gabriel: Disclosure completed | Zhenghua Zhu: Disclosure completed | Feng Li: Disclosure completed | Yuchao Zhao: Disclosure completed | Guanzhong Wang: Disclosure completed | Rosario Perez: Disclosure completed | Shaodong Li: Disclosure completed | Tony Wang: Disclosure completed | Bob Zhang: Disclosure completed