Diabetic nephropathy (DN) occurs in approximately 20-40% of the type 2 diabetes (T2D) global population. It has always been a challenge to find translatable, reliable and robust animal disease models for diabetic nephropathy − but the monkey model of diabetes with the progressive development of complications that resembles all the disease characteristics in humans can be considered as one of the most clinically translatable animal disease model for diabetic nephropathy.
Obesity occurs spontaneously in captive monkeys with similar characteristics to humans in the fat distribution pattern and adipocyte biology. such as pericardial fat which affects cardiac and coronary vasculature functions and central obesity. Central obesity is closely associated with the metabolic syndrome which affects 20 to 25% of human population. The metabolic syndrome also includes insulin resistance, dyslipidemia, fatty liver and hypertension and it is a major risk factor for diabetes and cardiovascular disease.
KBI has large colonies of cynomolgus macaque models of spontaneous and diet-induced obese with a wide range of metabolic disorders including metabolic syndrome, diabetes and other related comorbidities. The diet-responsive colonies of obese cynomolgus macaques induced by KBI proprietary Western-type of high fat diet (HFD). In these monkeys, our HFD predominantly incudes central obesity and the metabolic syndrome effects with a greater propensity to diabetes, non-alcoholic fatty liver disease, cardiovascular disease and chronic kidney disease. The following models of obesity and metabolic syndrome in cynomolgus monkeys are available at KBI:
· Spontaneous and diet-induced obesity with typical phenotype of the metabolic syndrome
· Spontaneous and diet-induced insulin resistance
· Spontaneous and diet-induced impaired glucose tolerance (pre-diabetic model)
· Spontaneous and diet-induced atherogenic dyslipidemia
· Spontaneous and diet-induced hypertension
KBI has a range of tools for the characterization of whole body and fat composition including dual energy X-ray absorptiometry (DEXA), anthropometry, BMI, abdominal circumference, skin-fold thickness and in-house laboratory assays for circulating lipids and biomarkers for obesity-associated disease.
KBI has various NHP models of cardiovascular disease including prolonged feeding with high fat diet (HFD), high fat and high fructose diet (HFHFrD) with added cholesterol and spontaneous hypertension with ageing. Hypertension is screened by the measurement of blood pressure (BP) with High Definition Oscillometry (HDO).
Diabetic retinopathy (DR) is the eye complication of diabetes. It affects up to 80% of patients who have suffered diabetes for more than 20 years. DR is caused by abnormalities in retinal blood vessels. The retinal vessel changes are initially non-proliferative in nature (non-proliferative DR, NPDR). With NPDR, the leakages of micro-vessels form macular edema. The micro-vessels could also close off, causing macular ischemia. Both forms of lesions could lead to the partial loss of vision or blurry. NPDR could gradually progress to more severe proliferative DR (PDR) as new blood vessels form in retina, which is called neovascularization. The newly formed vessels are usually fragile and often bleed into the vitroes. The bleeding could partially or completely block vision. Repeated disruption of retinal structure will lead to the scar formation and retinal detachment.
Most induced animal models of DR imitate only some features of DR, whereas spontaneous DR in NHPs recapitulates all the characteristics of human DR.
· Spontaneous DR has been identified in the diabetic monkeys at KBI. Both macular edema and ischemia were detected using fundus photograph (FP), fluorescein angiography (FA) and optical coherence tomography (OCT).
· Macular edema and ischemia can be also induced by laser at KBI and characterized using FP, FA and OCT.
KBI establishes Parkinson Disease (PD) Models through:
1. Systemic MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Administration
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.
Anti-glomerular basement membrane (GBM) glomerulonephritis accounts for 20% of all cases of rapidly progressive glomerulonephritis (GN) in adult humans. The end-stage renal disease develops in 40-70% of patients who have nephritis mediated by anti-GBM antibodies. Multiple immune components including cytokines and resident chemokines, macrophage recruitment, T lymphocytes, and immune complex deposition have been implicated in other glomerular diseases are now explored for their association with diabetic nephropathy. Furthermore, anti-GBM nephritis shares several common downstream molecular mechanisms and targets with lupus nephritis making the anti-GBM nephritis animal model another relevant and effective model for lupus nephritis disease translation.
At KBI, anti-GBM GN can be induced in the cynomolgus monkey model by immunization with type IV collagen. The cynomolgus nephritis model provides translational value to examine cellular and immune-mediated mechanisms of glomerulonephritis and pathogenesis of crescents, mesangial hypercellularity, interstitial fibrosis, and proteinuria. Furthermore, the cynomolgus macaque models of glomerulonephritis and diabetic nephropathy demonstrate comparable albuminuria, immune-mediated inflammatory targets, and renal morphological changes with human patients, suggesting that these common biomarkers and endpoints are useful for evaluating disease severity and treatment efficacy.
KBI has the following models of immune-induced nephritis and assessment tools:
· Normal cynomolgus monkeys
· Intact or Unilateral nephrectomy
· Induction: Nephritogenic Type IV Collagen
· Endpoint measurements: 24-hour urine proteinuria, Measurement of anti-NC1 antibody titer in serum and urine sample and GFR measurement by inulin clearance
· Kidney biopsy for: Standard histomorphology (H&E, PAS and PAM staining), IF staining for anti-monkey IgG, IgA and C3 and IHC staining for α-SMA and CD68
Diabetes is a major disease affecting more than 400 million people globally. Like in humans, type 2 diabetes in monkeys often occurs with ageing or obesity starting from insulin resistance (IR) or impaired glucose tolerance to overt diabetes due to the failure of pancreatic β-cells. The pathogenesis and histology of β-cell failure in monkeys are particularly similar to those in humans.
Myocardial infarction and heart failure are leading causes of the mortality worldwide. The NHP model of myocardial ischemia/reperfusion injury is very unique for the evaluation of new therapeutics (particularly protein products and gene therapies) to clinical application devoid of inter-species variations.
KBI has various models of ischemic-reperfusion by blocking and releasing the left anterior descending (LAD) artery. The ischemia and reperfusion injury is monitored by the ST elevation (STEMI) in ECG, plasma levels of creatine kinase (CK) and lactate dehydrogenase (LDH), and can be further examined by gross morphology and histopathology.
Age-related macular degeneration (AMD) is a common eye disease that leads to the central vision loss among people age over 50. There are two types of AMD: dry (atrophic) and wet (neovascular or exudative). Most AMD starts as the dry type. Ten to 20% of AMD patients will progress to wet AMD.
AMD models at KBI are:
· Spontaneous in aged monkeys
· Blue light-induced (dry AMD)
· Argon laser-induced CNV (wet AMD)
The blood vessel leakage and retinal neovascularization are confirmed using fluorescein angiography (FA) and optical coherence tomography (OCT). Retinal lesions of CNV are determined and characterized using imaging analysis of FA.