Recombinant soluble apyrase APT102 inhibits thrombosis and intimal hyperplasia in vein grafts without adversely affecting hemostasis or re‐endothelialization

Abstract

Summary Background Occlusion of vein grafts (VGs) after bypass surgery due to thrombosis and intimal hyperplasia (IH) is a major clinical problem. Apyrases are enzymes that scavenge extracellular ATP and ADP and promote adenosine formation at sites of vascular injury and hence have potential to inhibit vein graft pathology. Objectives We examined the effects of recombinant soluble human apyrase, APT102, on platelets, smooth muscle cells (SMCs), and endothelial cells (ECs) in vitro and thrombosis and IH in murine VGs. Methods SMC and EC proliferation and migration were studied in vitro. Inferior vena cava segments from donor mice were grafted into carotid arteries of recipient mice. Results While potently inhibiting ADP-induced platelet aggregation and VG thrombosis, APT102 did not impair surgical hemostasis. APT102 did not directly inhibit SMC or EC proliferation, but significantly attenuated the effects of ATP on SMC and EC proliferation. APT102 significantly inhibited SMC migration, but did not inhibit EC migration, which may be mediated, at least in part, by inhibition of SMC, but not EC, migration by adenosine. At 4 weeks after surgery, IH was significantly less in VGs of APT102-treated mice than in control VGs. APT102 significantly inhibited cell proliferation in VGs, but did not inhibit re-endothelialization. Conclusions Systemic administration of a recombinant human apyrase inhibits thrombosis and IH in VGs without increasing bleeding or compromising re-endothelialization. These results suggest that APT102 has the potential to become a novel, single-drug treatment strategy to prevent multiple pathological processes that drive early adverse remodeling and occlusion of VGs.

DNAse-dependent, NET-independent pathway of thrombus formation in vivo

“…Additional studies are required to determine if activation of neutrophil occurs before their binding to the injured endothelium and to identify the signaling pathway explaining how down-regulation by adenosine could prevent the accumulation of neutrophils at the site of injury. Y. Ji et al have reported that systemic administration of a recombinant apyrase inhibits thrombosis smooth muscle cell migration and intimal hyperplasia in vein grafts without increasing bleeding or compromising re-endothelialization (22). To confirm that point, additional experiments are required to decipher the role played by (ATP-activated) neutrophils in hemostasis.…”

In VivoDetection of Extracellular Adenosine Triphosphate in a Mouse Model of Traumatic Brain Injury

“… 45 The elimination-phase half-life is ∼36 h in mice. 46 Animals were injected with 1 mg/kg of APT102 (APT Therapeutics, Inc., St. Louis, MO) by tail vein injection before the initial isoflurane induction. 47 Vehicle-treated animals received tris-buffered saline as a control.…”

Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies

“…Notably, there were no safety or toxicity concerns when APT102 treatment was protracted after resolution of colitis in vivo (115). Additional studies reported on the safety profile of this molecule in the vascular setting (116,117). However, since CD39 also plays an important role in tumor development and progression (99,(118)(119)(120)(121) and inhibition of effector immune responses against pathogens (99,122,123), the safety of long-term treatments aimed at restoring the levels of this ectoenzyme in the context of autoimmune diseases should be considered and carefully evaluated.…”