Obesity is major risk factor underlying diabetes, cardiovascular disease (CVD), chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH), together they impose serious health problems worldwide. Kunming Biomed International (KBI) has established both spontaneously obesity and high fat diet (HFD)-induced obesity in a large cohort of non-human primate (NHP) cynomolgus monkeys. These two different types of obesity models closely resemble the etiologies (hyperphagia and overconsumption of fat) and phenotypes (diagram below) as seen in humans. As the phenotypes (e.g., adipose tissue browning) and lipid metabolism (e.g., lipoproteins) in NHPs resembles those in humans with not or little species difference, these obesity models can provide more reliable and accurate prediction for the effects of a new drug in future clinical use.
Retinal eye diseases, such as diabetic retinopathy and age-related macular degeneration, are highly prevalent in the middle-aged and aged population. Retinal gene therapy offers the best hope for the sustained effective treatment of these eye diseases with minimal adverse effects. Now KBI has successfully established a technique of subretinal injection in non-human primate (NHP) as shown below. This is very important for the translation of a gene therapy to clinical application because subretinal injection delivers gene therapy to the target location and avoid off-target effects and adverse reactions in other locations. Now KBI has successfully established a technique of subretinal injection in non-human primate (NHP) as shown below. This is very important for the translation of a gene therapy to clinical application because subretinal injection delivers gene therapy to the target location and avoid off-target effects and adverse reactions in other locations.
Chronic Kidney Disease (CKD) can lead to renal failure. Currently the global prevalence of CKD continues to increase, and it has become a major cause of death and imposed a heavy burden to the public health. Diabetes and hypertension are the major causes of the development of CKD. KBI has characterized the CKD models in the non-human primate (NHP) cynomolgus monkey, which is highly similar to the features of diabetic CKD in humans. KBI’s NHP CKD models have been used to evaluate the investigational new drugs, some of which have successfully entered clinical trials.
According to WHO's report, more than 1 billion populations worldwide suffer from central nervous system (CNS) diseases including Alzheimer's disease, multiple sclerosis, epilepsy, Parkinson's disease and stroke. Despite enormous efforts, there is still no effective therapy for CNS diseases. One of major obstacles is whether or not a new drug can cross the blood-brain barrier to reach the designed target within the CNS. This requires the collection of cerebrospinal fluid (CSF) to assess the pharmacokinetics of the test drug within the CNS. However, this procedure is very difficult in animals because CSF can only be obtained from cannulation to the spinal cord under anesthesia.
Today KBI announce that The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates published in the prestigious journal DIABETES, Dr. Shaohui Ji, scientist form Kunming Biomed International as the co-first author. Nonalcoholic steatohepatitis (NASH) is associated with increased incidence of cirrhosis, hepatocellular carcinoma and cardiovascular disease. There are currently no approved medications for treating nonalcoholic fatty liver disease (NAFLD) and NASH. Fibroblast growth factor 21 (FGF21) is an important metabolic regulator, and has shown beneficial effects on the improvement of NAFLD and NASH. However, due to the short half-life in vivo, the development of wild-type FGF21 as a drug is challenging. B1344 is developed as a site-specific PEGylated human FGF21 analog. The reengineering of FGF21 leads to significantly improved biopharmaceutical properties, extended half-life and pharmacokinetics, and reduced immunogenicity. In collaboration with Professor MA Xiaohui at Tasly Pharmaceutical Co. Ltd and scientists at Kunming Biomed International (KBI), a team of scientists led by Professor LI Yu from Shanghai Institute of Nutrition and Health, CAS demonstrate that in L6 myoblasts with the overexpression of βKlotho/FGFR1c, B1344 was sufficient to activate βKlotho/FGFR1c signaling and appears to show stronger potency in terms of the activation of downstream signaling than that of wild-type FGF21. Moreover, using high-fat diet-fed cynomolgus monkeys and methionine- and choline-deficient diet-induced mice of NASH models, scientists demonstrated the salutary effects of B1344 on the protection against the progression of nonalcoholic steatohepatitis. In the cynomolgus monkeys with NAFLD, administration of B1344 for 11 weeks caused a remarkable reduction of hepatic fat content, inflammation and fibrosis as evidenced by magnetic resonance imaging and histological analysis of the liver biopsy. Meanwhile, the metabolic benefits of B1344 on lowering body weight, blood glucose, glucose tolerance and improving plasma lipid profile were observed in the monkey, whereas no obvious changes of the bone mineral density were observed. Consistently with the monkey data, the anti-NASH effects were also observed in choline-deficient diet-induced rodent model. This study provides preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans This work was published online in Diabetes on April 30, 2020, DOI:10.2337/db20-0209 as a research article entitled “The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates”. “This reflects the fact that KBI emphasizes science and promotes value-driven CRO services to our partners from both industry and academia”, commented from Bob Zhang, CEO of KBI. “In addition to NASH model in NHPs, KBI’s other human disease-like animal models including obesity, diabetes, diabetic complications such as heart failure, kidney diseases and retinal eye diseases have also provided tremendous values to our worldwide collaborators in facilitating their R&D programs. KBI commits to the continuous investment and development of pharmacology models and technology platforms based on our deep scientific understanding of NHP models and collective expertise from our strategic partners and consultants”, further commented from Dr. Zhang. Related website: https://diabetes.diabetesjournals.org/content/early/2020/04/30/db20-0209.long
Sanofi, a global pharmaceutical company and long-term partner of KBI, recently published their research work performed in collaboration with KBI in high impact journals. Scientists from Sanofi global diabetes research and translational medicine team and KBI systematically studied the mechanism of action of dual agonists of GLP-1 /glucagon receptors on glucose, body weight and energy homeostasis using KBI’s diet-induced NHP model of metabolic syndrome. Both teams also worked together and revealed the pharmacological effect of Sanofi’s novel GLP-1/glucagon receptor co-agonists in body weight and glycemic control in obese and diabetic NHPs. The research work has been published in the recent issues of Diabetes, Obesity and Metabolism [20(8):1836-1851], and in Endocrinology [159(8):3105-3119, 2018]. “These two papers published by Sanofi in the prestigious journals further demonstrate the translational value of KBI’s unique monkey models with metabolic dysregulations”, said Zhiming Ding, KBI’s CSO. “We are grateful to Sanofi who has selected KBI as the preclinical service provider, and KBI is proud of being the partner of a global leader in the field to pursue scientific excellence. KBI commits to providing translational NHP disease models and pharmacology solutions to accelerate our collaborator’s drug discovery and development programs”, further commented by Bob Zhang, CEO of KBI.
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.
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