Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial.

RATIONALE: Pulmonary arterial hypertension (PAH) remains a progressive and eventually lethal disease characterized by increased pulmonary vascular resistance because of loss of functional lung microvasculature, primarily at the distal (intracinar) arteriolar level. Cell-based therapies offer the potential to repair and regenerate the lung microcirculation and have shown promise in preclinical evaluation in experimental models of PAH. OBJECTIVE: The Pulmonary Hypertension and Angiogenic Cell Therapy (PHACeT) trial was a phase 1, dose-escalating clinical study of the tolerability of culture-derived endothelial progenitor cells, transiently transfected with endothelial nitric oxide synthase, in patients with PAH refractory to PAH-specific therapies. METHODS AND RESULTS: Seven to 50 million endothelial nitric oxide synthase-transfected endothelial progenitor cells, divided into 3 doses on consecutive days, were delivered into the right atrium via a multiport pulmonary artery catheter during continuous hemodynamic monitoring in an intensive care unit setting. Seven patients (5 women) received treatment from December 2006 to March 2010. Cell infusion was well tolerated, with no evidence of short-term hemodynamic deterioration; rather, there was a trend toward improvement in total pulmonary resistance during the 3-day delivery period. However, there was 1 serious adverse event (death) which occurred immediately after discharge in a patient with severe, end stage disease. Although there were no sustained hemodynamic improvements at 3 months, 6-minute walk distance was significantly increased at 1, 3, and 6 months. CONCLUSION: Delivery of endothelial progenitor cells overexpressing endothelial nitric oxide synthase was tolerated hemodynamically in patients with PAH. Furthermore, there was evidence of short-term hemodynamic improvement, associated with long-term benefits in functional and quality of life assessments. However, future studies are needed to further establish the efficacy of this therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00469027.

Hydroxybutyl Chitosan Polymer-Mediated CD133 Antibody Coating of Metallic Stents to Reduce Restenosis in a Porcine Model of Atherosclerosis.

Antibody-coated stents to capture circulating endothelial progenitor cells (EPCs) for re-endothelialization appear to be a novel therapeutic option for the treatment of atherosclerotic disease. Hydroxybutyl chitosan (HBC), a linear polysaccharide made from shrimps and other crustacean shells, is biocompatible, nontoxic, and hydrophilic, making it ideal for biomedical applications. In this study, HBC was explored for the immobilization of anti-CD133 antibodies. We demonstrated that CD133 antibodies mediated by HBC were successfully coated on cobalt-chromium alloy discs and metal stents. The coating was homogeneous and smooth as shown by electronic microscopy analysis. Balloon expansion of coated stents did not cause cracking or peeling. The HBC discs promoted CD133+ EPCs and human umbilical vein endothelial cell growth in vitro. The CD133 antibody-coated but not bare discs bound CD133+ EPCs in vitro. Implantation of CD133 antibody-coated stents significantly inhibited intimal hyperplasia and reduced restenosis compared with implantation of bare stents in a porcine model of atherosclerosis. These findings suggest HBC is a valuable anchoring agent that can be applied for bioactive coating of stents and that CD133 antibody-coated stents might be a potential therapeutic alternative for the treatment of atherosclerotic disease.

Growth factor-induced therapeutic neovascularization for ischaemic vascular disease: time for a re-evaluation?

PURPOSE OF REVIEW: Therapeutic angiogenesis and arteriogenesis represent an alternative treatment modality for patients with advanced ischaemic coronary or peripheral artery occlusive disease, who are unsuitable for standard revascularization procedures. RECENT DEVELOPMENTS: Proof-of-concept evidence for therapeutic growth factor, both gene and protein-mediated neovascularization was provided in animal models of chronic myocardial and hindlimb ischaemia. Early human, phase I, trials utilizing the prototypical growth factor families, vascular endothelial growth factor and fibroblast growth factor, documented safety and suggested improvements in anginal symptoms and functional status. Large, randomized, placebo-controlled phase II/III clinical trials have, however, yielded variable results as such studies have suffered from significant limitations in therapeutic approach or design, which limits the ability to draw firm conclusions. SUMMARY: Future trials must incorporate robust delivery strategies and address issues of study design including proper patient selection. Laboratory-based refinements in therapy, including a focus on the promotion of arteriogenesis and the modification of patient 'endotheliopathy', will all further enhance the potential of therapeutic neovascularization strategies.