Warren Sherman

Percutaneous Cell Delivery Into the Heart Using Hydrogels Polymerizing In Situ

Heart disease is the leading cause of death in the US. Following an acute myocardial infarction, a fibrous, noncontractile scar develops, and results in congestive heart failure in more than 500,000 patients in the US each year. Muscle regeneration and the induction of new vascular growth to treat ischemic disorders of the heart can have significant therapeutic implications. Early studies in patients with chronic ischemic systolic left ventricular dysfunction (SLVD) using skeletal myoblasts or bone marrow-derived cells report improvement in left ventricular ejection function (LVEF) and clinical status, without notable safety issues. Nonetheless, the efficacy of cell transfer for cardiovascular disease is not established, in part due to a lack of control over cell retention, survival, and function following delivery. We studied the use of biocompatible hydrogels polymerizable in situ as a cell delivery vehicle, to improve cell retention, survival, and function following delivery into the ischemic myocardium. The study was conducted using human bone marrow-derived mesenchymal stem cells and fibrin glue, but the methods are applicable to any human stem cells (adult or embryonic) and a wide range of hydrogels. We first evaluated the utility of several commercially available percutaneous catheters for delivery of viscous cell/hydrogel suspensions. Next we characterized the polymerization kinetics of fibrin glue solutions to define the ranges of concentrations compatible with catheter delivery. We then demonstrate the in vivo effectiveness of this preparation and its ability to increase cell retention and survival in a nude rat model of myocardial infarction.

An Open Label Dose Escalation Study to Evaluate the Safety of Administration of Non-Viral SDF-1 Plasmid to Treat Symptomatic Ischemic Heart Failure

Rationale: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. Objective: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. Methods and Results: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ⩽40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3–61 minutes]; 30 mg: 31 minutes [22–74 minutes]) and quality of life (15 mg: –16 points [+1 to –32 points]; 30 mg: –24 points [+17 to –38 points]) over baseline. At 12 months, improvements in symptoms were maintained. Conclusions: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.

Dual catheter technique for the treatment of severe coronary artery perforations

Objectives: To evaluate the outcome of patients with coronary perforations who were treated with the dual catheter approach. Background: Coronary artery perforation is a grave complication of percutaneous coronary intervention (PCI) with high mortality and morbidity. Treating a coronary artery perforation with two catheters through dual access enables a rapid delivery of covered stent or coils to the vessel, without losing control of the perforation site. Methods: We retrospectively reviewed all patients who had a severe coronary perforation during a PCI in our center, and compared outcomes of patients treated with the dual versus the traditional single guiding catheter approach. Results: Between April 2004 and October 2008, 13,466 PCIs were performed in Columbia University – New York Presbyterian Medical Center. There were 33 documented cases of coronary perforations during that period of time (0.245%), among these, 26 were angiographically severe (Ellis type 2 or 3 perforations). Eleven patients were treated acutely with a dual catheter technique whereas the other fifteen patients were treated using a single guiding catheter. In the dual catheter group one patient expired after emergent CABG (9.1%), and four patients underwent emergent paricardiocentesis (36.4%). In patients treated with single catheter, there were three deaths (20%), two surgical explorations (13.3%), eight emergent pericardiocenthesis (53.3%), and one event of severe anoxic brain damage (6.7%). Conclusion: The dual catheter technique is a relatively safe and reproducible approach to treat a PCI induced severe coronary artery perforation, and may improve outcome compared to historical series.

Transcatheter injection-induced changes in human bone marrow-derived mesenchymal stem cells.

Human mesenchymal stem cells (hMSC) are being administered by direct intramyocardial (IM) injection into patients with myocardial dysfunction with an objective to improve clinical status. However, surprisingly little attention has been directed to qualifying hMSC functionality beyond simple viability. In particular, the transit of hMSCs through a small-caliber needle lumen, the final fluidic pathway for all IM injection devices, may be especially prone to inducing unwarranted effects on cell function. This study evaluated the changes in clonogenicity, gene expression, and cytokine secretion that may be induced in hMSC (20 million/ml) by injection through a 26-gauge Nitinol needle at two different flow rates compared to noninjected control samples. Results indicated that hMSC viability and colony forming unit (CFU) formation was not altered by changes in injection rate, although a trend toward lower titers was noted at the higher flow rate, for the specific batch of hMSCs studied. The gene expression and cytokine analysis data suggest that delivering a suspension of MSCs through narrow lumen needles may marginally alter certain gene expression programs, but that such in vitro effects are transient and not translated into measurable differences in protein production. Gene expression levels of four cytokines (bFGF, SDF-1, SCF, VEGF) were significantly different at 400 μl/min, and that of all cytokines were significantly different at 1600 μl/min when compared to controls (p < 0.05). These changes were less pronounced (statistically insignificant for most cases, p > 0.05) and, in certain instances directionally opposite, at 72 h. However, no differences in the amounts of secreted bFGF, VEGF, or TGF-β were detectable at either of the two time points or flow rates. We infer that intramyocardial administration by transcatheter techniques is unlikely to interfere with the machinery required for cell replication or secretion of regulatory and other growth factors, which are the mainstays of MSC contribution to cardiac tissue repair and regeneration.

Myocyte replacement therapy: skeletal myoblasts.

Skeletal myoblasts function as precursors to adult skeletal myocytes. More so than other muscle progenitors, their capacity for de novo self-renewal and their positive functional effects in the cardiac environment have been demonstrated, even though they do not attain a cardiomyocyte phenotype. Autologous skeletal myoblasts are easily procured by established methods and can be administered into diseased myocardium safely and without technical difficulty, features that at this time set them apart from any other myogenic cell. Clinical studies in patients with chronic myocardial disease have consistently reported modest improvements in ventricular function and clinical status. Data from the Myogenesis Heart efficiency and Regeneration Trial (MYOHEART) trial are currently being evaluated. Larger, randomized, placebo-controlled studies in patients with congestive heart failure due to postinfarction systolic left ventricular dysfunction are under way, such as Myoblast Autologous Grafting in Ischemic Cardiomayopathy (MAGIC) and Multicenter Study of the Safety and Cardiovascular Effects Of Myoblasts in Congestive Heart Failure (MARVEL). The future role of skeletal myoblasts in the clinical setting will be determined by the results of randomized trials as well as by the investigation of subsequent generations of myoblasts, engineered for enhanced efficacy.

Catheter-Based Endomyocardial Delivery of Mesenchymal Precursor Cells Using 3D Echo Guidance Improves Cardiac Function in a Chronic Myocardial Injury Ovine Model

The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 106 (n = 10), 75 × 106 (n = 9), or 225 × 106 (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3±3% in 225M MPCs vs. −5±4% in the control group, p < 0.01) and wall thickening in both infarct (4±4% in 225M MPCs vs. −3±6% in the control group, p = 0.02) and border zones (4±6% in 225M MPCs vs. −8±9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.

Commercialization of trials for peripheral artery disease

Cell-based clinical studies for peripheral arterial dis-ease (PAD) are moving forward at a brisk pace, to early pivotal trials, a fact that offers considerable hope and encouragement for the cardiovascular regenera-tive fi eld. Doors are opening to novel agents, further insights and important questions, while some aspects of clinical development, such as multiple dosing, opti-mal administration techniques and bio-equivalence testing, remain to be addressed. The regenerative approach to advanced PAD is dynamic, and open to creative input from industry and clinical scientists, but mandatory for the success of the clinical trial process and commercialization of its products, is that a level of collaboration be undertaken among those invested in this fi eld, particularly regarding optimiza-tion of trial design and recruitment. The International Society for Cellular Therapy (ISCT) focuses on driving the translation of scien-tifi c research and developing technology platforms essential to cell therapy. In keeping with its goal of expediting the development of cell therapies and advancing global patient access, ISCT has given priority to creating forums directed toward emerg-ing cell therapeutics and commercialization perspec-tives. This goal takes on particular importance as pivotal cell therapy studies have commenced regard-ing acute myocardial infarction, refractory angina, congestive heart failure and PAD. Results will have signifi cant bearing on subsequent trials. Therefore, ensuring that clinical trial design and endpoints are well selected and that investigators have the tools to evaluate comparative cell types and select the most appropriate among them, is crucial to the fi eld at this time. These imperatives align well with key missions of ISCT: to foster open-code development of specifi c cell products targeting specifi c diseases, and to pro-vide regulatory agencies with a background and data integral to their decision-making processes. With the Cardiovascular Research Foundation (CRF), ISCT convened a strategic Clinical Development Focus Group in January 2011 at the Sixth International Conference on Cell Therapy for Cardiovascular Dis-eases (IC3D), involving experts from academia and industry for a focused discussion on clinical studies in advanced PAD.