KBI has more than 1,000 monkeys at stages of pre-diabetes, overt diabetes and diabetes with complications for the evaluation of new drugs: · Pre-diabetes (hyperinsulinemia, impaired glucose tolerance, insulin resistance) · Type 2 diabetes with hyperinsulinemia and hypoinsulinemia · Diabetic nephropathy · Diabetic retinopathy · Diabetic Neuropathy A full array of comprehensive tools are well established for the detailed characterization at various stages including: · Clinical chemistry for metabolic profiling · Oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT) and insulin tolerance test (ITT) · Oral lipid tolerance test (OLTT) and meal tolerance test (MTT) · Graded glucose infusion (GGI) · Hyperinsulinemic-euglycemic clamp · GI-bypass and gastric emptying
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
The KBI monkey models of spontaneous intraocular hypertension and laser-induced ocular hypertension closely mimic the glaucoma in humans with typical high intraocular pressure (IOP) and optic nerve pathology. These two models provide reliable validation of therapeutic treatments for high IOP and associated neuropathology to guide clinical trials.
Spinal Cord Injury (SCI) are critically needed to facilitate translation of laboratory discoveries to clinical applications. KBI has designed a spinal cord impactor and operating procedures specific for producing a SCI model in monkeys to successfully evaluate the therapeutics for the treatment of SCI models.
KBI has established a step-wise screening system with the use of clinical chemistry, blood biomarkers, echocardiogram and myocardial MRI to characterize different types of heart failure (HF) with a large body of database. We have produced models of heart failure with either reduced ejection fraction (HFrEF, or systolic failure) or preserved ejection fraction (HFpEF, diastolic failure) from more than 1,000 prolonged HFD monkeys (Fig 1).
KBI has established a step-wise screening system specially for monkeys by the Slit-lamp test to identify and assess cataract with the use of Lens Opacities Classification System III (LOCS III).
Alzheimer disease (AD) is a progressive disorder that typically presents as severe loss of memory, particularly of episodic memory. Non-human primate (monkeys) models have superior values to other laboratory animals for the research on this neurodegenerative disease because the close similarities of their neural system to humans. KBI readily has a large cohort of aged monkeys available for the screening of AD-related indications which can be compared to their junior counterparts in-house. KBI is well paced to evaluate the progression of AD and therapeutic effects on this ageing-related disease with the Cambridge Neuropsychological Test Automated Battery (CANTAB) Facility specific for testing on cognitive functions in monkeys. We also have a monkey-specific maze for tests of learning and memory.
Myopia is a type of refractive disorder. KBI has screened a large cohort of monkeys and identified 10% to 13% myopia at an age of 5 years or older. We have a large cohort of monkeys with moderate to severe myopia available and they have been successfully used for the evaluation of various therapeutic treatments.
KBI has established a step-wise screening system to identify the dry eye disease (DED) in non-human primates (NHPs). This model has been successfully used for the evaluation of pharmacological efficacy, safety and pharmacokinetics. As illustrated below, a range of evaluations tools are available for the detailed evaluation of this eye disease at KBI, including the Schirmer's test, measurement of tear film breakup time (TBUT), staining of corneal fluorescein and examination of meibomian glands.
Induced-eye disease models: • OHT glaucoma • Normal IOP glaucomatous neurodegeneration • Retinal detachment • Uveitis • Optic neuropathy Optic Neuritis • Macular edema • Low vision Spontaneous eye disease models • Presbyopia • Cataract • Myopia • Dry eye