Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation

Abstract

Original Clinical Science-General Background. When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. Methods. The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 ± 10 seconds and 50 ± 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. Results. Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 ± 5 days after the first transplant) between the 2 arms (1.33 ± 1.10 versus 1.56 ± 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups. Conclusions. Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

“…The release and activation of multiple growth factors from peripheral and central tissues would initiate a program of diverse downstream cellular responses relating to metabolism, tissue repair, and regeneration. For example, ILB ® induces release of Hepatocyte Growth Factor (HGF) from sequestered stores [35,68], a growth factor known to be neuroprotective and to stimulate glucose transport, metabolism and oxidative stress [69,70].…”

“…While high molecular weight dextran sulfate possesses toxic effects, inducing cancer development and inflammation [31][32][33], ILB ® is a proven safe and well-tolerated LMW-DS. Previous studies showed that LMW-DS dose-dependently limits the instant blood-mediated inflammatory reaction (IBMIR) [34,35], inhibits E-selectin-mediated adhesion of neutrophils to endothelial cells [36,37], prevents adherence of peritoneal metastases [38], and improves the effectiveness of therapy and reduces mortality in patients with acute cerebral infarction treated with the thrombolytic agent urokinase [39]. Of particular mechanistic relevance to TBI, subcutaneous injection of ILB ® induces a rapid release of pharmacologically relevant levels of Hepatocyte Growth Factor (HGF) into the circulation in laboratory animals and healthy human volunteers, which may provide a neurotrophic stimulus to the injured central nervous system (CNS) [35].…”

Regulation of c-Jun NH2-Terminal Kinase for Islet Transplantation

“…Low molecular weight dextran sulfate (LMW-DS, MM 5000) is an alternative inhibitor of IBMIR [80,81,82,83,84]. An open randomized multicenter study showed that LMW-DS has a similar efficacy in inhibiting IBMIR to promote islet engraftment when compared with heparin [84]. Activated protein C (APC) is another potent inhibitor which exerts anticoagulant, anti-inflammatory, and antiapoptotic activities by acting directly on cells.…”

Unsurpassed Intrahepatic Islet Engraftment – the Quest for New Sites for Beta Cell Replacement

“…After transplantation, beta cell survival can be impaired by acute and/or chronic factors. Immediately when islets are injected, direct contact with the vascular system exposes them to an instant blood-mediated reaction (IBMIR) which contributes to early graft loss 15 –17 . In addition, there is a substantial risk of beta cell death due to acute hypoxia.…”