Kunming Biomed International (KBI), located in southwest China, is a contract research organization (CRO) providing preclinical research services, specialized on non-human primates. The core competency of KBI stems from our expertise in developing and running specialized primate animal models to test drug candidates and medical devices for their pharmacological effects and biocompatible repairs. A large animal colony combined with experienced research and scientific study teams can offer “one-stop service” which ensures quality and detail. We also conduct adjacency studies in PK/PD, in vivo pharmacology and preliminary toxicology. KBI offers cost effective study of the highest quality while applying the highest standards of animal welfare and animal ethics. KBI has already achieved AAALAC accreditation, and is working under GLP conditions.
KBI has a partner research institute - the National Engineering Research Center of Biomedicine and Animal Science (NERCBA), and close collaborations with Morningside portfolio companies and other leading pharmacology CROs in China.
At KBI, we are dedicated to elevate the standard of preclinical research services to the highest level. Recognized for our breadth of capabilities and professional expertise, KBI merges talent with technology to produce a preclinical research facility that exceeds our clients’ expectations. We have integrated years of experience with a host of successful processes and solid infrastructure that promise outstanding services across the spectrum.
Osteoarthritis (OA) is a global degenerative joint disease that affects over 10% of the world’s population aged 60 years or older. Despite the recent availability of more advanced imaging modalities, controlled investigations of structural and biochemical changes in human osteoarthritic joints are still restricted by the relative inaccessibility of diseased tissues for sampling and the ethical limitations in the use of sham interventions or placebo, and in obtaining control human tissues. Thus, animal OA models are used to study the disease pathogenesis and to evaluate the potential effects of various therapeutic agents intended for human/clinical use.
Spontaneous OA occurs in nonhuman primates and is known to affect over 65% of cynomolgus monkeys >15 years of age, and about 30% of cynos between 10-15 years old. The similarity between human and NHP OA in terms of age-related prevalence, clinical course and disease severity and, sequential anatomical and biomechanical degenerative changes make the cynomolgus macaque an excellent translational disease model for human OA. This model can be particularly useful to evaluate the pharmacodynamic action and therapeutic efficacy of novel pharmaceutical entities. Furthermore, the availability of behavioral, functional and activity assessment pain measures in the monkey disease model allows more effective characterization and investigation of OA pain response and modulation patterns following the administration of prospective pharmacological therapies that are intended for human/clinical use.
X-ray of the joints can be reliably performed at KBI for the screening of naturalistic arthritis models from KBI’s large population of aged cynomolgus monkeys. Typical x-ray changes characteristic of OA such as joint space narrowing, subchondral sclerosis, subchondral cyst formation, and osteophytes have been observed in our naturalistic cyno OA disease models. Furthermore, magnetic resonance imaging (MRI) can effectively be utilized at KBI for the longitudinal assessment of semi-quantitative and quantitative imaging endpoints, such as cartilage morphology and composition, of the affected joints and articular tissues.
Spontaneous Inflammatory Bowel Disease Model
An appropriate inflammatory bowel disease (IBD) experimental model is important for testing potential therapeutic agents and for investigating the mechanisms of pathogenesis. KBI utilizes colonoscopy to identify ulcerative colitis in NHP cohorts with characteristic clinical signs of chronic or recurrent inflammatory bowel disorders.
KBI screens for spontaneous ulcerative colitis in our non-human primate colony according to the following criteria:
· Chronic diarrhea for more than 6 months
· Chronic body weight loss in more than 3 months
· Fecal examination to exclude parasite infestation
· Endoscopy examination to confirm multiple and continuous colonic ulcers
· Endoscopic findings of colonic ulcers during the 2-month follow-up
· Biopsy findings of colonic crypts and mucosal damage
Non-alcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic fatty liver disease (NAFLD) is recognized as a common liver disorder that represents the hepatic manifestation of the metabolic syndrome, a variably defined aggregate of disorders related to obesity, insulin resistance, type II diabetes, hypertension and hyperlipidemia. NAFLD has been considered to refer to a spectrum of diseases of the liver ranging from steatosis (i.e., fatty infiltration of the liver) to nonalcoholic steatohepatitis or NASH (i.e., steatosis with inflammation and hepatocyte necrosis) to cirrhosis. NASH is regarded as the more aggressive form of liver injury that carries a risk for progressive fibrosis, cirrhosis, and end-stage liver disease, and is, thus, deemed to result in significant morbidity and mortality. NASH is characterized histologically by the presence of portal and lobular mononuclear and polymorphonuclear infiltrate inflammation, hepatocellular ballooning degeneration, fibrosis, and hepatocellular necrosis. In the most severe state, NASH may be associated with cirrhosis. Furthermore, hepatocellular carcinoma (HCC) is a documented complication in an as yet unknown percentage of cases of NASH with cirrhosis in humans.
Progression to NASH has been observed in 20% to 30% of patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and the transition from NAFLD to NASH has been considered to involve disruption of multiple compensatory pathways within the liver. Nevertheless, recent investigations have argued that NAFLD and NASH are likely distinct not only from a histological but also from a pathophysiological standpoint. Different animal models have so far been investigated and utilized in order to gain valuable insights on the mechanisms involved in NAFLD and NASH development. However, in order to facilitate effective therapeutic target identification and efficacy testing, as well as, to enable efficient establishment of translational biomarkers, it is critical to identify or develop translational animal models that can more accurately match the etiological pattern, metabolic changes, and clinico-pathological presentation of these diseases in humans.
At KBI, high fat diet induced NHP liver disease models have been developed and characterized in a large cohort (over 1,500 male cynomolgus monkeys). They have similar disease progression and pathological features seen in humans. Based on our MRI, ultrasound 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.
Our screening protocol includes a comprehensive assessment of the animals' clinical history and database; regular diabetic and lipid profiling, liver-specific biochemical function tests, and other physiologic tests. 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.
KBI has developed hypertensive models from high fat diet (HFD) induced cadiovascular disease NHP models. Utilizing High Definition Oscillometry (HDO), blood pressure (BP) measurements are performed to screen for hypertension in NHPs.
HDO is an non-invasive approach to blood pressure measurement that allows the real-time visualization of oscillometric pulse waves during the opening of an artery as the pressure decreases in an occluding cuff.
HDO has the following advantages: · Fast processors (32 bit) · High definition sensors · Easy operation for animals HDO measurement has been validated in comparison to direct BP measurement: · Normal Systolic Pressure: 110-120 mmHg · Hypertension: Systolic >140 mmHg Diastolic>90 mmHg
Acute Myocardial Injury (AMI) and Ischemic Reperfusion Injury Model
Myocardial infarction and heart failure are rated as the leading cause of mortality worldwide. Myocardial ischemia/reperfusion injury has gained recognition as a clinically relevant model for myocardial infarction studies. For this reason, the cynomolgus monkey model of myocardial ischemia/reperfusion provides translational value that is vital to investigate the acute and chronic pathophysiological processes in myocardial infarction, as well as, to develop, evaluate, and optimize available and prospective therapeutic interventions.
At KBI, the transient Acute Myocardial Injury (AMI) is induced in the cynomolgus monkey by left anterior descending (LAD) ligation-reperfusion. The model correlates well with the post-AMI induction ECG changes of ST elevation myocardial infarction (STEMI), the time-course changes in cardiac enzymes (CK and LDH), as well as, the consequent gross morphological and histopathological changes.
Obesity and Metabolic Syndrome
Obesity occurs spontaneously in captive adult NHPs, particularly in cynomolgus and rhesus macaques, with proven similarities to man in the distribution pattern and metabolism of adipose tissues making these species excellent models for the condition in humans. Moreover, the intra-abdominal adipocytes from the cynomolgus macaque are metabolically similar to human adipocytes. Quantifiable pericardial fat, the secretion of which may directly influence cardiac and coronary vasculature functions, is distinctly observed in macaques in contrast to rodents. Finally, socio-environmental factors tend to influence adipose tissue distribution similar to humans. Obesity phenotypes induced by high-fat diet corroborated that, similar to man, NHPs could develop metabolic syndrome.
Metabolic syndrome, which refers to the co-occurrence of obesity, insulin resistance, dyslipidemia, and hypertension with associated cardiovascular risk factors, affects 20 to 25% of the entire world human population. The close phylogenetic relatedness of monkeys to man with regard to feed responses, lipid-lipoprotein profiles, and genotype make them desirable translational disease models for studying human bioenergetics, obesity, metabolic syndrome, diabetes mellitus, and associated co-morbidities.
KBI has the reputable advantage of having large colonies of naturally-occurring/spontaneous, as well as, diet-induced obese, pre-diabetic/ diabetic and dysmetabolic cynomolgus macaque models that offer translational value for the investigation of pathophysiological pathways and the therapeutic potential of novel pharmacological agents targeting obesity, metabolic syndrome, diabetes mellitus and related comorbidities.
At KBI, diet-responsive colonies of cynomolgus macaques are fed with a proprietary high-fat diet, which closely replicates the Western-type diet. The HFD-induced obesity phenotypes are similar to man in terms of the central fat distribution pattern as well as, the effects of diet on lipid metabolism, insulin secretion and gluco-regulation. The obese monkeys characteristically develop insulin resistance and hyperlipidemia.
The following models of obesity and metabolic syndrome in cynomolgus monkeys are available at KBI:
· Spontaneous/Naturalistic and Diet-Induced Obesity / Metabolic Syndrome
· Spontaneous and Diet-Induced Insulin Resistance
· Spontaneous and Diet-Induced Impaired Glucose Tolerance/ Pre-Diabetic Model
· Naturalistic and Diet-Induced Dyslipidemia, and Atherogenic Dyslipidemia
Overall, NHPs have been the preferred model for the study of whole body obesity as well as some aspects of fat distribution. Multidimensional evaluations including the assessment of whole body and fat composition using Dual Energy X-Ray Absorptiometry (DEXA), anthropometry (BW, BMI, abdominal circumference, skin-fold thickness) and clinical chemistry biochemical parameters are performed at KBI for obesity evaluation and therapeutic efficacy outcome assessment.
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