Abstract
We report the results of an independent laboratory’s tests of novel agents to prevent or reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse, BioBreeding diabetes prone (BBDP) rat, and multiple autoimmune disease prone (MAD) rat models. Methods were developed to better mimic human clinical trials, including: prescreening, randomization, blinding, and improved glycemic care of the animals. Agents were suggested by the research community in an open call for proposals, and selected for testing by an NIDDK appointed independent review panel. Agents selected for testing to prevent diabetes at later stages of progression in a rodent model were a STAT4 antagonist (DT22669), alpha1 anti-trypsin (Aralast NP), celastrol (a natural product with anti-inflammatory properties), and a Macrophage Inflammatory Factor inhibitor (ISO-092). Agents tested for reversal of established T1D in rodent models were: alpha1 anti-trypsin (Aralast NP), tolerogenic peptides (Tregitopes), and a long-acting formulation of GLP-1 (PGC-GLP-1). None of these agents were seen to prevent or reverse type 1 diabetes, while the positive control interventions were effective: anti-CD3 treatment provided disease reversal in the NOD mouse, dexamethasone prevented T1D induction in the MAD rat, and cyclosporin prevented T1D in the BBDP rat. For some tested agents, details of previous formulation, delivery, or dosing, as well as laboratory procedure, availability of reagents and experimental design, could have impacted our ability to confirm prior reports of efficacy in preclinical animal models. In addition, the testing protocols utilized here provided detection of effects in a range commonly used in placebo controlled clinical trials (for example, 50% effect size), and thus may have been underpowered to observe more limited effects. That said, we believe the results compiled here, showing good control and repeatability, confirm the feasibility of screening diverse test agents in an independent laboratory.
Highlights
The non-obese diabetic (NOD) mouse was discovered in 1980 [1], and the BBDP rat in 1974 [2]
A major limitation of the effort to model the human disease using the NOD mouse or BB rat is the lack of understanding of the human disease
The NOD model is impacted by its environment, and it has been well-known that diabetes incidence rates can vary among animal facilities [32]
Summary
The MAD rat, (formerly LEW.1WR1) was reported as an inducible model in 2005 [3]. Since these rodents been used as models of autoimmune destruction of insulin-producing beta cells. A major limitation of the effort to model the human disease using the NOD mouse or BB rat is the lack of understanding of the human disease. We cannot know which features of the rodent diseases are relevant until we know the important players in human pathogenesis. Correlative or descriptive studies using human specimens from clinical research provide hints as to which mechanisms might be contributing to pathogenesis and to therapeutic responses in humans
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