Stem cells: Potential to transform CVD care

Excitement abounds in the cardiology community surrounding the possibility of new, potentially effective stem cell therapies for the treatment of CVD.

“The stem cell/regenerative medicine field is probably the most exciting area that we have right now. It’s like the beginning of a new era for the management of CVDs, both for diagnosis and treatment, and it has only been around for a few years,” said Carl J. Pepine, MD, professor in the division of cardiovascular medicine, University of Florida, Gainesville, and Chief Medical Editor of Cardiology Today. “In addition to cardiac and vascular recellularization, we are also acquiring tools to approach patient-specific diagnosis and treatment strategies using the patients’ own cells.”

Douglas W. Losordo, MD, adjunct professor of medicine at Northwestern University Feinberg School of Medicine, said this new era will bring about major changes for those with conditions such as chronic HF.

“Application of cell-based therapies to treat chronic diseases, including cardiac disease, will have a major impact on medicine, transforming previously ‘permanent’ damage into reversible conditions. This means that the inexorable progression of disability often associated with conditions such as HF will no longer be the rule. I view this era as being similar to the first use of antibiotics, which transformed uniformly fatal conditions like pneumococcal pneumonia into manageable illnesses,” Losordo said. “Medical students of coming decades will likely look back and wonder how it was possible that a heart attack could have been associated with permanent disability.”

Growing knowledge base

An increasing amount of novel research is emerging. Recent mixed trial results — some encouraging, some suggesting altered directions for research — have added to the enthusiasm. Barriers exist, but the technology is advancing with notable amounts of new research being presented.

Three of five stem cell clinical trials presented as late-breaking clinical trials at the American Heart Association Scientific Sessions in November demonstrated favorable results: SCIPIO, POSEIDON and ALCADIA.

Initial 2-year follow-up results, along with complete 4-month results from the SCIPIO trial, demonstrated benefits of using autologous c-Kit–positive cardiac stem cells in patients with HF of ischemic etiology who underwent CABG. The findings were presented by Roberto Bolli, MD, chief of cardiovascular medicine and director of the Institute of Molecular Cardiology at the University of Louisville.

In this first-in-human, phase 1, randomized, open-label trial, researchers isolated cardiac stem cells from harvested cardiac tissue from patients with HF who underwent CABG. Researchers grew additional cells, then reinfused them back into the same patient from whom they were harvested (n=20). Controls (n=13) did not receive any treatment. Patients were followed for 2 years. Patients who received cardiac stem cells experienced significant improvement in ejection fraction vs. the control patients who showed no significant change in ejection fraction at 1 year. Increases of 7% at 4 months, 8.1% at 1 year and 12.9% at 2 years were seen in the treated patients, according to a press release. Treated patients also experienced a reduction in infarct size and an increase in viable tissue that persists at least 1 year. Two-year follow-up data were only available in six patients.

“We found that at 1 year — and now we are also seeing it at 2 years — there was a remarkable improvement in ejection fraction, a decrease in the size of the scar by MRI, an increase in valuable tissue by MRI, an improvement in New York Heart Association Class and in quality of life as measured by the Minnesota Living with Heart Failure Questionnaire. We found striking results — more than we expected — in this small group of patients. This is a small study and it is not conclusive evidence, but it is encouraging,” Bolli told Cardiology Today.

Larger multicenter studies are needed to confirm the findings, Bolli said.

The POSEIDON randomized trial compared the safety and efficacy of autologous and allogeneic mesenchymal stem cells (MSCs) as therapy in patients with left ventricular dysfunction due to ischemic cardiomyopathy. In this 30-patient, randomized comparison without a placebo control, researchers concluded that transendocardial injection of allogeneic and autologous MSCs were both associated with low rates of treatment-emergent serious adverse events. MSC injection overall — including results from both types of cells — favorably affected patient functional capacity along with quality of life and ventricular remodeling.

Another study, ALCADIA, presented by Naofumi Takehara, MD, of Kyoto Prefectural University of Medicine, Japan, found that in the seven patients with ischemic cardiomyopathy included in the study, use of autologous human cardiac-derived stem cells was safe. The patients also experienced improved maximum oxygen consumption by an average of about one-third (P=.0308).

Two other trials presented at the recent AHA Scientific Sessions did not yield positive results with primary endpoints; however, a subgroup analysis in each offered more information.

In the TIME randomized trial, Jay H. Traverse, MD, of the Minneapolis Heart Institute at Abbott Northwestern Hospital and University of Minnesota Medical School, and colleagues found that administration of intracoronary bone marrow mononuclear cells at either 3 or 7 days after PCI for patients with STEMI had no significant effect on recovery of LV function — global or regional — as compared with placebo. However, younger patients assigned cell therapy at 7 days after the event showed significant improvement in ejection fraction compared with placebo, the researchers found in a prespecified subgroup analysis.

In the 4-month, 200-patient SWISS-AMI study, Daniel Sürder, MD, of the University of Zurich in Lugano, Switzerland, and colleagues looked at intracoronary infusion of bone marrow mononuclear cells compared with controls given at 1 or 4 weeks after primary PCI in patients with STEMI. The researchers found that LV function as assessed by MRI did not improve. In a subgroup analysis of patients reperfused within 4.5 hours of the onset of chest pain, researchers found that this approach may offer some benefit.

Earlier in 2012, at the American College of Cardiology 61st Scientific Sessions in March, researchers presented results for the FOCUS-CCTRN trial. Results showed no significant differences at 6 months in change in LV end-systolic volume assessed by echocardiography, maximal oxygen consumption or reversible defect on single-photon emission CT between patients with chronic ischemic heart disease along with HF and/or angina who received stem cell therapy vs. controls. However, patients who received stem cell therapy, compared with placebo, had a small but significant increase in LVEF (2.7%). Another significant finding was that LVEF change correlated with the number of CD34+ and CD133+ cells in bone marrow during cell implantation, according to the researchers.

These aforementioned data also show that the autologous bone marrow stem/progenitor cell product prepared using an automated system for the CCTRN trials is active, according to Pepine.

A shifting focus

Stem cell research for CVDs has only been around for about 15 years.

“The field of CV cell therapy is now over 15 years old, having been inaugurated by the identification of the tissue repair capabilities of adult endothelial progenitor cells by Asahara and Isner in 1997. The early controversy surrounding this work has been replaced by increasing enthusiasm generated by the data supporting the clinical potential of cell-based therapies to offer a true chance to ‘turn back the clock’ on CVD, not only by attenuating progression but also by potentially reversing prior damage,” Losordo said.

The focus of stem cell-related research has shifted from studying applications with skeletal muscle cells in trials started in the early 2000s to studies of bone marrow-derived cells to adipose-derived cells to cardiac-derived stem cells to combination cells.

Skeletal cells in early trials appeared promising in terms of their ability to contract when transplanted into the heart, but danger for arrhythmias basically ended that field of endeavor, Pepine said.

According to Bolli, use of embryonic stem cells is basically nonexistent. “Those cells, in my opinion, have no clinical application because of the problems related to tumor formation and rejection, which essentially prohibits their clinical use.”

Next, progenitor cells, bone marrow-derived cells, came forward. These trials are still ongoing. The European Cooperative Union is providing funding to conduct a 3,000-patient trial using bone marrow-derived mononuclear cells post-MI to prevent mortality. The BAMI trial will be led by Andreas Zeiher, MD, of the department of internal medicine IV, University of Frankfurt, Germany.

“The University of Frankfurt has the largest single-center experience in the world with bone marrow-derived stem cell administration, and this upcoming trial is a testament to the durability of the bone marrow-derived cells,” Pepine said.

When adipose tissue-derived cells started to gain entry into the clinical trials, it was shown that these cells are highly abundant and easy to access. Also, stem/progenitor cells appear to be very robust in their function, as opposed to bone marrow cells that tend to be depressed with chronic systemic disease, such as HF.

Then about 3 years ago, the first cardiac-derived stem cell emerged in clinical research.

The notion of using a combination of cells has come forward in the past 2 years, in which combining two different cell types, for example, MSC plus a c-Kit cell (either autologous, allogeneic or mixed in origin), may have more promise than using only one cell, as was shown in a single preclinical study.

“The question then at the end of this past 10 years is what cell type is best? The answer is that we don’t know yet,” Pepine said.

Directions for new research

One focus of upcoming research aims to answer questions about the benefits and drawbacks of using autologous cells, which come from the patient, compared with using allogeneic cells, which come from someone else.

“There are a number of important studies ongoing or planned,” Losordo said. “For autologous stem cells, the RENEW study consists of two phase 3 pivotal trials that are testing the use of autologous CD34+ stem cells for treatment of refractory angina.”

RENEW is a prospective, randomized, double blind, active-control and unblinded standard of care controlled study, according to details at ClinicalTrials.gov. Researchers are working to determine the efficacy and safety of targeted intramyocardial delivery of autologous CD34+ cells for increasing exercise capacity during standardized exercise testing in patients with refractory angina pectoris and chronic myocardial ischemia, as stated in the official title of the study.

Bolli and colleagues are planning a phase 2 study of c-Kit–positive cells for treatment of chronic HF as a follow-up to the successful SCIPIO trial. The phase 2 trial proposed is currently seeking a sponsor.

Cardio3 BioSciences in Belgium is sponsoring a study for the autologous “cardiopoietic” cell in patients with HF — CHART-1. The study is currently recruiting patients, according to ClinicalTrials.gov.

Marc S. Penn, MD, PhD, director of research, Summa Cardiovascular Institute, Summa Health System, professor of medicine and integrative medical science, Northeast Ohio Medical University, discussed his ongoing research with colleagues using the patient’s own stem cells without the need for actually delivering stem cells. The phase 2 trial is called STOP-CHF.

“We have shown that [stromal cell-derived factor-1] induces stem cell activation and homing to the site of injured tissue. Our work documents that this repair system is present in virtually all injured tissues. We have completed a successful phase 1 clinical trial in chronic HF and have ongoing phase 2 clinical trials investigating the potential for [stromal cell-derived factor-1] to treat patients with symptomatic HF, critical limb ischemia and sternal wound healing. If successful it will demonstrate that stem cell-based tissue repair can be induced without the need for delivering stem cells; rather, activation of the patients own stem cells is sufficient,” Penn said in an interview.

Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute, and colleagues are working with allogeneic cell therapy. Marbán views this as a major direction for the future.

“The cell therapy field needs to move away from the concept of stemness. Therapeutic regeneration just doesn’t work that way. Cells are biological factories that produce potent cocktails of secreted factors. Rather than engrafting long term, adult cells do their thing in the first few weeks after transplantation. They set in motion a cascahenryde of self-healing which can result in durable benefits even after the transplanted cells have disappeared. The realization that the benefits do not rely on long-term engraftment forms the scientific rationale for universal-donor (allogeneic) cell therapy, which is a major wave of the future,” Marbán told Cardiology Today.

One such trial in post-MI patients, ALLSTAR, is presently in phase 1 with allogeneic cardiosphere-derived cells. The randomized, placebo-controlled, phase 2 portion of ALLSTAR is anticipated to start later in 2013, with scar size reduction as a primary goal. Timothy D. Henry, MD, director of research at the Minneapolis Heart Institute Foundation, and Rajendra (Raj) Makkar, MD, director of interventional cardiology and cardiac catheterization laboratory at Cedars-Sinai Medical Center, are the national co-principal investigators of ALLSTAR. “This trial has the potential to be a real game-changer, by shifting patients from high risk (large scars, with likely progression to HF) to low risk (small scars, preserved ventricular structure and function),” Marbán said.

In other ongoing research, NeoStem Inc. is conducting a large phase 2 study of bone marrow CD34+ cells for the treatment of MI, with results expected this year, according to Losordo. The PreSERVE-AMI study is sponsored by Amorcyte LLC, a subsidiary of NeoStem Inc. The prospective, randomized, double blind, placebo-controlled trial will study the safety and efficacy of intracoronary artery administered autologous bone marrow-derived stem cells, AMR-001, an autologous CD34+ selected cell product, in patients with acute MI.

Osiris Therapeutics Inc. recently issued a press release announcing that its multicenter, human clinical stem cell trial for the drug Provacel has been cleared by the presiding independent safety board to begin enrolling patients at higher doses of the drug. The development of the drug, a stem cell treatment for patients with MI is part of a strategic alliance with Boston Scientific Corp.

Companies including Angioblast, Athersys, Cytori and Mesoblast also are conducting research in this arena.

Other directions for new research

An exciting prospect is the potential use of molecular imaging strategies to assess cell survival, homing and migration in patients receiving stem cell treatments. A recent study published by Joseph C. Wu, MD, PhD, director of the Stanford Cardiovascular Research Institute, and Bojan Vrtovec, MD, from the Advanced Heart Failure and Transplantation Center, UMC Ljubljana, Slovenia, in Circulation Research in January provided 5-year follow-up results of a randomized clinical trial administering G-CSF mobilized CD34+ stem cells labeled with 99mTc-hexamethylpropylene-amine oxyme for treatment of nonischemic dilated cardiomyopathy. In this study, scintigraphical gamma imaging was used to track cell location following delivery through the detection of the 99mTc radioisotope and cell homing to the myocardium was correlated to functional outcome in patients. Patients who demonstrated poor myocardial homing of CD34+ cells by scintigraphy were not observed to improve LV function at any time during the 5-year follow-up. By comparison, patients with high levels of myocardial homing demonstrated improved parameters of cardiac function for up to 1 year following receipt of cell therapy.

This is the first study to correlate myocardial homing of stem cells with functional outcome. “We anticipate future use of cell imaging modalities will likely refine the methods of stem cell delivery for treatment of cardiac disease and improve our understanding of stem cells’ contribution toward patient recovery following injury of the myocardium,” Wu told Cardiology Today.

In addition, Wu and colleagues have also pioneered use of induced pluripotent stem cells (iPSCs) to understand disease mechanisms underlying common genetic cardiac disorders such as hypertrophic cardiomyopathy and dilated cardiomyopathy. Recent studies from the Wu lab have employed iPSC technology to build “disease in a dish” models for hypertrophic cardiomyopathy, dilated cardiomyopathy and other cardiac disorders, allowing for drug screening on patient-specific cardiomyocytes in vitro for the first time.

“The use of patient-specific iPSCs has also been a revolution for personalized medicine, enabling the assessment of an individual’s response to a tailored medical regimen at the single cell level without clinical administration,” Wu said. By deriving a library of genetically diverse iPSCs from patients of varying ages, sexes and ethnic backgrounds, the researchers aim to take a “clinical trial in a dish” approach to accelerate the drug development process.

Although recent advances in cellular reprogramming of somatic cells to patient-specific iPSCs have enabled in vitro modeling of human genetic disorders for pathogenic investigations and therapeutic screens, most cardiomyocytes derived from these patient-specific iPSCs in cultures are fetal-like in terms of their electrophysiological, metabolic and other functional properties. Thus, using iPSC-derived cardiomyocytes to model most adult-onset heart disease remains challenging due to the uncertainty regarding the ability of relatively immature iPSC-derived cardiomyocytes to fully recapitulate adult disease phenotypes, according to HS Vincent Chen, MD, PhD, associate professor at Sanford-Burnham Medical Research Institute in La Jolla, Calif., and Daniel P. Kelly, MD, scientific director at the Sanford-Burnham Medical Research Institute in Orlando, Fla.

“Our recent findings that adult-like metabolic milieu is needed to properly model an adult-onset, inherited cardiac disease, named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), indicates the importance of adult-like metabolism of iPSC-derived cardiomyocytes in creating a clinically relevant cardiac disease model with iPSCs,” Chen and Kelly said.

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“Most ARVD/C patients don’t know they have a heart problem until they are in their late teens or early 20s. Patients are usually diagnosed only at advanced stages of the disease or after sudden death — when it’s too late. This makes it difficult for researchers to study how ARVD/C evolves or to develop curative treatments. As a result, ARVD/C patients, often young athletes, usually received an electronic defibrillator to prevent sudden death, yet no treatment options available to them to slow down the disease progression, which may eventually lead to heart transplant.”

By converting patients’ fibroblasts to iPSCs, these researchers can now derive patient-specific iPSC-derived cardiomyocytes to create the “disease in a dish” model to study an inherited cardiac disease. However, they note, made straight from iPSCs, these newly made heart cells are mostly immature. This raises questions about whether they truly represent a disease that does not appear until adulthood.

Scientists and clinicians from Sanford-Burnham Medical Research Institute and Johns Hopkins University teamed up and spent more than 3 years to recapitulate the defects in ARVD/C, but only when they induced adult-like metabolism in these patient-specific iPSC-derived cardiomyocytes. This is an important breakthrough considering that ARVD/C symptoms usually do not arise until young adulthood. Yet, the stem cells the researchers are working with are embryonic in nature. “For that reason, this newly published ARVD/C model is likely more relevant to human ARVD/C than other models. It’s therefore better suited for studying the disease and developing new therapies. Many other cardiac disease models have also been published with patient-specific iPSCs. This ‘disease in a dish’ technology would likely lead to better understanding of various cardiac pathologies and, most importantly, develop novel therapeutic strategies for slowing down disease processes,” Chen and Kelly said.

Barriers to overcome

Barriers to stem cell therapy for cardiac diseases, including ethical issues and funding, exist.

“Some prominent clinical trials of ischemic heart disease have been performed with cell products that have never been optimized, in terms of dosage or formulation or efficacy, in relevant animal models. Poorly conceived clinical trials pollute the field, making it hard for investors and clinicians and regulators to separate the wheat from the chaff. There is something real in cell therapy, but it’s not easy to tease apart what’s real from what’s poorly conceived and premature,” Marbán said.

In December, Pepine attended the 7th Annual World Stem Cell Summit in West Palm Beach, Fla. “It was an interesting meeting because they ran simultaneous sessions and had a mixture of scientists, business people, venture capitalists, governmental officers, policy-setters, ethicists, everyone,” he said. “Wherever you live, everybody is now looking for more and more innovative funding mechanisms that focus on business as opposed to their federal sector. I am not saying that the federal government isn’t putting money into stem cell therapy research, the scientists and business people working in this space are just looking at different areas for their research funding.”

According to Bolli, a major barrier is lack of support for phase 2 and phase 3 studies. “The support is hard to find for many stem cell types that are promising. These new cell therapies are in the infamous ‘valley of death,’ the chasm between phase 1 and phase 3 trials,” he said.

“It’s hard to tell if [sponsors] are becoming more difficult to find than they were before. I’m not sure how to make that comparison,” Bolli said.

Future predictions

Despite barriers, experts see a significant and exciting future in this field.

“Cardiac stem cells are promising because now we are able to isolate them and expand them from endomyocardio biopsies. This means treatment is potentially available in just about every patient with HF,” Bolli said in an interview. “If the SCIPIO phase 2 trial confirms the results of SCIPIO phase 1, this could very well become a major advancement in the treatment of HF, but it will be a minimum of 5 years, maybe longer, before this therapy becomes clinically available on a widespread basis.”

The induced pluripotent stem cells could also become a clinical tool in the future. Now, the most likely candidates for clinical use are adult stem cells, particularly the one or more subtypes of bone marrow cells and cardiac stem cells. “Those will be the first cells we will see in clinical application,” Bolli said.

“Stem cell therapy offers the potential to prevent or treat cardiac dysfunction in patients with ischemic heart disease,” Penn said. “Our success at restoring antegrade flow in patients with acute MI has resulted in great success in helping patients survive; however, we need strategies to improve cardiac function in order to prevent many of these patients from developing chronic HF. We have demonstrated that the use of allogeneic stem cells may offer significant benefit and have the potential to be available in the cardiac catheterization laboratory when the patient has primary PCI for STEMI or PCI for NSTEMI.

“Research on the mechanisms of stem cell-based tissue repair has demonstrated that there is an endogenous stem cell repair process that can repair injured myocardium. The future of stem cell therapy will be focused on the development of drugs or genes that will allow us to induce the body to repair itself without the need to pull stem cells out of the patient’s body and then redeliver them,” Penn said.

“As is typical for paradigm-shifting therapies, stem cells will be tested first in patients with the most severe conditions. Once there is sufficient evidence of safety and bioactivity, then more modest conditions will be approached,” Losordo said.

Disclosure: Bolli reports no relevant financial disclosures. Losordo reports no relevant financial disclosures. The research by Chen and Kelly is supported by grants from the California Institute of Regenerative Medicine and the NIH. Kelly reports serving on scientific advisory boards for Lilly and Pfizer and a research grant from Takeda. Marbán reports significant financial interest in Capricor, the company that is performing the ALLSTAR trial. Penn is named as an inventor on patent applications filed for the use of SDF-1 to treat CVD that have been licensed by Juventas Therapeutics Inc., sponsor of the STOP-CHF trial; as such, Penn is eligible for royalties from and equity in Juventas Therapeutics. Penn is the founder and chief medical officer of Juventas Therapeutics, as such, he is a paid consultant. Pepine reports no relevant financial disclosures. Wu reports no relevant financial disclosures.