Abstract
Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity. The aim of this study was to investigate the efficiency of two batches of BL-7010 to interact with gliadin, essential vitamins and digestive enzymes not previously tested, and to assess the ability of the copolymer to reduce gluten-associated pathology using the NOD-DQ8 mouse model, which exhibits more significant small intestinal damage when challenged with gluten than HCD4/DQ8 mice. In addition, the safety and systemic exposure of BL-7010 was evaluated in vivo (in rats) and in vitro (genetic toxicity studies). In vitro binding data showed that BL-7010 interacted with high affinity with gliadin and that BL-7010 had no interaction with the tested vitamins and digestive enzymes. BL-7010 was effective at preventing gluten-induced decreases in villus-to-crypt ratios, intraepithelial lymphocytosis and alterations in paracellular permeability and putative anion transporter-1 mRNA expression in the small intestine. In rats, BL-7010 was well-tolerated and safe following 14 days of daily repeated administration of 3000 mg/kg. BL-7010 did not exhibit any mutagenic effect in the genetic toxicity studies. Using complementary animal models and chronic gluten exposure the results demonstrate that administration of BL-7010 is effective and safe and that it is able to decrease pathology associated with gliadin sensitization warranting the progression to Phase I trials in humans.
Highlights
Celiac disease (CD) is an autoimmune, chronic small intestinal enteropathy triggered by the consumption of gluten, composed of gliadins and glutenins, in genetically predisposed individuals expressing the HLA genes DQ2 or DQ8 [1,2]
The interaction of biotinylated Polymer A with vitamins, bovine serum albumin (BSA) and digestive enzymes was evaluated by surface plasmon resonance (SPR)
These results suggest that BL-7010 may interact with human serum albumin but this is expected to have negligible effect on malnutrition and safety as discussed below. Due to their low molecular weights, the vitamins were evaluated at the high concentrations of 10 and 100 mM, while gliadin was injected as a positive control at a concentration of 100 nM
Summary
Celiac disease (CD) is an autoimmune, chronic small intestinal enteropathy triggered by the consumption of gluten, composed of gliadins and glutenins, in genetically predisposed individuals expressing the HLA genes DQ2 or DQ8 [1,2]. Development of the disease may be accompanied by an unknown environmental risk factor [3,4]. Immune responses in these individuals mainly involve reaction with gliadin-derived peptides, such as the 33-mer [5], that have been modified by the native human enzyme, transglutaminase 2 (TG2), allowing greater binding affinity to HLA DQ2 and DQ8 haplotypes on gut immune cells [6]. There are a number of therapeutic approaches under development for CD Some of these include intestinal permeability modulators and endopeptidases that cleave gliadin peptides making them less immunogenic [17]. HLA-DQ2 blockers) and vaccination with gluten components [18]
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