Goal 2: Reduce Human Disease

Cellular therapy of Blood Diseases

Can modification of either autologous or allogeneic immune cells allow effective treatment of blood diseases and infection with acceptable rates of toxicity?

Submitted by (@marymh)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Although targeted therapy is generally applied to the use of small molecules that target specific genes or proteins of diseased cells, it is now possible to target immune cells against specific diseases through genetic modification. This provides desired antigen-specificity to powerful cell-mediated cytotoxicity effects. Small studies show impressive results both in blood cancers and viral infections refractory to other therapies. Toxicity and efficacy vary with the diseases being treated and the cell products used. In addition, new approaches to genetically-modify blood stem cells are being evaluated to prevent viral infection, i.e. HIV, or correct hematopoietic stem cell derivatives, and these approaches could cure diseases for which good treatments are not currently available.

Feasibility and challenges of addressing this CQ or CC :

Both preclinical and clinical studies are needed to identify optimal cell types and gene constructs, use of “universal” donors, and magnitude and durability of clinical effects. Effective infrastructure to provide the right cells at the right time is necessary to test clinical efficacy.

Name of idea submitter and other team members who worked on this idea : Mary Horowitz

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Goal 2: Reduce Human Disease

Gene Therapies to Revitalize/Regenerate Cardiac Function

There is a need to examine the use of recombinant DNA to the heart for correction of genetic abnormalities or restoration of normal signaling pathways to prevent heart failure. However, gene therapy is a complex process and more studies are needed in which tissue targeting, route of delivery, regulation of target gene expression, therapeutic dose, and identification of robust biomarkers are further investigated.

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Successful gene therapy could restore or improve the condition of heart failure patients, especially when medications have been unsuccessful.

Feasibility and challenges of addressing this CQ or CC :

There have already been human trials of gene therapy in heart failure patients with positive outcomes.

Improvements in cardiac revascularization and medical therapies have significantly reduced cardiovascular-related deaths; however, the number of patients developing heart failure (HF) has steadily increased. One explanation is that surgery and medical therapies are palliative, but do not address the molecular pathogenesis of HF.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 3: Advance Translational Research

Deriving Cardiac Elements from Pluripotent Human embryonic Stem Cells for Heart Reconstitution

to date, the existing markets lack a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential, which has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged human heart in cardiovascular disease.

Submitted by (@xuejunparsons)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Given the limited capacity of the heart for self-repair or renewal, cell-based therapy represents a promising therapeutic approach closest to provide a cure to restore normal heart tissue and function for CVD. There is no evidence that adult stem/precursor/progenitor cells derived from mature tissues, such as bone marrow, cord blood, umbilical cord, mesenchymal stem cells, patients’ heart tissue, placenta, or fat tissue, are able to give rise to the contractile heart muscle cells following transplantation into the heart. Despite numerous reports about cell populations expressing stem/precursor/progenitor cell markers identified in the adult hearts, the minuscule quantities and growing evidences indicating that they are not genuine heart cells and that they give rise predominantly to non-functional smooth muscle cells rather than functional contractile cardiomyocytes have caused skepticism if they can potentially be harnessed for cardiac repair. In recent years, reprogrammed or trans-differentiated adult cells, as a result of being backed by excess sum of government and private funding, have been rekindled as the adult alternates. However, major drawbacks such as abnormal gene expression, accelerated aging, immune rejection, not graftable, and extremely low efficiencies, have severely impaired the utility of reprogrammed or trans-differentiated somatic cells as viable therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Derivation of pluripotent human embryonic stem cells (hESCs) from the IVF leftover embryos has brought a new era of cellular medicine for the heart. The intrinsic ability of a hESC for both unlimited self-renewal and differentiation into clinically-relevant lineages makes it a practically inexhaustible source of replacement cells for human tissue and function restoration. Therefore, it has been regarded as an ideal source to provide a large supply of functional human cells to heal the damaged or lost tissues that have naturally limited capacity for renewal, such as the human heart and the human brain. Although a vast sum of NHLBI funding has been spent on looking for adult alternates, such as reprogramming and trans-differentiation of fibroblasts or mature tissues, so far, only human cardiac stem/precursor/progenitor cells derived from embryo-originated hESCs have shown such cellular pharmacologic utility and capacity adequate for myocardium regeneration in pharmaceutical development of stem cell therapy for the damaged human heart.

Name of idea submitter and other team members who worked on this idea : Xuejun Parsons

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Goal 3: Advance Translational Research

Maximizing anti-tumor immunity following allogeneic HCT with biomarkers

Allogeneic hematopoietic cell transplantation (allo-HCT) is one of the most effective forms of tumor immunotherapy available to date. Allo-HCT can be life-saving for patients with aggressive malignancies that cannot be cured through other strategies. The immunotherapeutic efficacy of allo-HCT depends on donor T cell recognition of alloantigens on leukemic cells, which is known as the graft-versus-tumor effect (GVT). No ...more »

Submitted by (@sophpacz)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Allo-HCT represents the only curative therapy for a number of malignant disorders but often results in serious complications, including GVHD. Because GVHD is such a potentially devastating post-transplant complication and because we want to be able to separate GVHD from the GVT effect, it is crucial to try to determine a specific biological pattern link to the favorable GVT effect. The focus of this critical challenge will be to develop a novel, non-invasive GVT signature in patients undergoing HCT. If successful, this will have a major impact, because a GVT-specific proteomic signature may facilitate the clinical therapeutic decision of rapid taper of immunosuppression or increased immunotherapies. The ability to identify patients who will not develop GVT early post-transplant has important therapeutic consequences, including preventative care with donor-lymphocyte infusion (DLI) or tumor-specific vaccines or T cells expressing chimeric antigen receptors (CARs). Equally important is the identification of patients who will develop GVT without GVHD, potentially enabling more rapid tapering of immunosuppressive regimens and thereby promoting even more the GVT reaction as well as reducing long-term toxicity in these patients. With this diagnostic tool, the HCT community may plan to develop preemptive therapeutic trials. In addition, the biomarkers may represent potential GVT-specific therapeutic targets to maximize GVT and/or immunotherapies.

Feasibility and challenges of addressing this CQ or CC :

Using proteomics, several GVHD biomarkers were recently identified and validated. For example, high suppression of tumorigenicity 2 (ST2) plasma concentrations were significantly associated with the incidence of GVHD and transplant-related mortality in recipients of unmanipulated graft and cord blood transplants. Consequently, the Blood and Marrow Transplant Clinical Trial network is currently pursuing therapeutic interventions for newly diagnosed GVHD patients based on GVHD biomarkers risk-stratification. Thus, discovering and validating biomarkers post-HCT is feasible. However, the challenges with GVT-specific biomarkers are three-fold: 1) the absence of phenotype, as the only way to define clinical GVT without GVHD, is the absence of relapse and no GVHD post-HCT; 2) the paucity of samples to study GVT, ideally samples following DLI or nonmyeloablative conditioning preparative regimens that permit stable engraftment of donor hematopoietic cells but have little or no direct tumoricidal activity should be available; and 3) the relative lack of knowledge of the biology of GVT. These represent important challenges to solve. In sum, the recent successes of cancer immunotherapies, particularly for the treatment of hematological malignancies, have stimulated interest in the potential widespread application of these approaches, and biomarkers to predict and monitor the responses are required.

Name of idea submitter and other team members who worked on this idea : Sophie Paczesny

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Goal 2: Reduce Human Disease

Human Lung Progenitor Cells, Lung Epithelial Differentiated iPSCs, and Therapeutics

What are the biological properties and key surface markers of human lung progenitor cells and lung epithelial differentiated iPSCs? How can these cell populations be targeted for therapeutic purposes, including regenerative therapy?

Submitted by (@skrenrich)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Cystic Fibrosis Foundation

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Goal 3: Advance Translational Research

Genome Editing and Gene Therapy

There is a critical need for the establishment of strategies that will determine the efficacy, safety, and toxicity of genome editing techniques specifically in hematologic diseases.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Goal 3: Advance Translational Research

The Designation of Human Cardiac Stem Cell therapy Products for Human Trials or First-in-Human Studies

For successful pharmaceutical development of cardiac stem cell therapy, the human cardiac stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials.

Submitted by (@xuejunparsons)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

For successful pharmaceutical development of cardiac stem cell therapy, the human cardiac stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials. Moving stem cell research from current studies in animals into human trials must address such practical issues for commercial and therapeutic uses: 1) such human stem cells or their cardiac derivatives must be able to be manufactured in a commercial scale; 2) such human stem cells and their cardiac derivatives must be able to retain their normality or stability for a long term; and 3) such human stem cells must be able to differentiate or generate a sufficient number of functional or contractile cardiomyocytes for repair. Those practical issues are essential for designating any human cardiac stem cells as a human cardiac stem cell therapy product for investigational new drug (IND)-filing and entry into clinical trials. So far, the therapeutic effects, if any, of human cardiac stem cells in the existing market, including those derived from patients’ heart tissues, were mediated by protective or tropic mechanism to rescue dying host cardiomyocytes, but not related to myocardium regeneration.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent breakthrough stem cell technologies have demonstrated the direct pharmacologic utility and capacity of pluripotent human embryonic stem cell (hESC) therapy derivatives for human CNS and myocardium regeneration and, thus, have presented the hESC cell therapy derivatives as a powerful pharmacologic agent of cellular entity for a wide range of CNS and heart diseases. The hESC cardiomyocyte cell therapy derivatives by novel small molecule induction provide a large scale of high quality human cardiomyocyte source for myocardium regeneration and, thus, meet the designation of human stem cell therapy products in plasticity, specificity, and stability for commercial development and human trials or first-in-human studies in cardiovascular diseases.

Name of idea submitter and other team members who worked on this idea : Xuejun Parsons

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Goal 2: Reduce Human Disease

Treatment of Major Depression in Patients with Heart Failure

Major depression (MD) is common in patients with heart failure, and it is an independent risk marker for functional decline, hospitalization, and mortality. Two large trials have shown that it can be difficult to treat. SADHART-CHF, a double-blind, placebo-controlled RCT (n=469), found that sertraline was not efficacious for MD in HF. MOOD-HF (n=372) showed that escitalopram was not efficacious. Smaller trials of cognitive-behavioral ...more »

Submitted by (@freedlak)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Major depression causes considerable emotional distress and functional impairment. It follows a chronic or recurrent course in many cases, and untreated episodes can last for months or even years. When superimposed on chronic heart failure, major depression can accelerate functional decline, diminish quality of life, and increase the risks of hospitalization and mortality. Effective treatment of depression can, at minimum, improve quality of life. Treatment may also decrease the risk of adverse medical outcomes, but RCTs will be needed to evaluate the potential medical benefits of treating depression in HF.

Feasibility and challenges of addressing this CQ or CC :

Cognitive behavior therapy is the most promising approach tested so far, but there have been few trials of this intervention, any other psychotherapeutic treatment for depression, or antidepressant medications other than sertraline or escitalopram for major depression in HF. Additional phase II trials may be needed in order to identify the most promising approaches for testing in larger, multicenter RCTs.

Name of idea submitter and other team members who worked on this idea : Kenneth E. Freedland, PhD

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Goal 3: Advance Translational Research

Exploring Future Cardiovascular Medicine: Heart Precursors Directed from Human Embryonic Stem Cells for Myocardium Regeneration

Cardiovascular disease (CVD) is a major health problem and the leading cause of death in the Western world. Currently, there is no treatment option or compound drug of molecular entity that can change the prognosis of CVD.

Submitted by (@xuejunparsons)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The human stem cell is emerging as a new type of pharmacologic agent of cellular entity that is much more complex in structure, function, and activity than the conventional drug of molecular entity, which is usually comprised of simple chemicals or compounds. Since the etiologies of most diseases that involve both molecular and cellular processes are much more complex than simple chemicals or molecules, conventional chemical drugs are often severely limited by the molecular entity of the compound that usually targets or blocks certain pathological molecular pathways, which would otherwise be harmful to common molecular pathways shared in normal cellular processes of vital tissues and organs, thus, cause severe toxic side effects that may outweigh the benefits. For instance, a drug for weight loss may cause severe damage to the heart. In addition, the therapeutic effects of conventional drugs of molecular entity provide only temporary or short-term symptomatic relief but cannot change the prognosis of disease. As a result, millions of molecular leads generated in mainstream of biomedical research from animal studies and studies of other lower organisms have vanished before even reach clinical trials, or for a few lucky ones, in clinical trials. In the last few decades, despite of many animal leads, no drug of molecular entity has ever been approved by FDA as a new treatment for heart disease and failure for humans.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: In contrast, the human stem cell has the potential for human tissue and function restoration that the conventional drug of molecular entity lacks. The ability of a human stem cell, by definition, to both self-renew and differentiation makes it a practically inexhaustible source of replacement cells for many devastating or fatal diseases that have been considered as incurable, such as neurodegenerative diseases and heart diseases. The pharmacologic activity of human stem cells is measured by their extraordinary cellular ability to regenerate the tissue or organ that has been damaged or lost, such as the heart in the case of human cardiac stem cells. Therefore, the pharmacologic utility of human stem cells cannot be satisfied only by their chaperone activity, if any, to produce trophic or protective molecules to rescue existing endogenous host cells that can simply be accomplished by a drug of molecular entity. The embryo-originated human embryonic stem cells (hESC) are not only pluripotent, but also incredibly stable and positive, proffering unique revenue to generate a large supply of cardiac lineage-committed stem/precursor/progenitor cells as well as functional cardiomyocytes as adequate human myocardial grafts for cell-based therapy. Currently, the hESC cardiomyocyte therapy derivatives provide the only available human cell sources with adequate capacity to regenerate the contractile heart muscles, vital for heart repair in the clinical setting.

Name of idea submitter and other team members who worked on this idea : Xuejun Parsons

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Goal 3: Advance Translational Research

Next generation of cellular blood products for clinical use

What advancements in our understanding of hematopoietic stem cell differentiation can be combined with practical developments in novel processing and storage technologies to develop the next generation of transfused blood therapeutics? There is a dearth of tools to evaluate the efficacy of transfused blood products, although this is the most commonly employed therapeutic procedure in the US. There is also no financial ...more »

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The management of blood transfusions in the clinical setting is undergoing drastic changes in the US with the realization that “more” is not better and that transfusion of red blood cells while life-saving in hemorrhagic settings may be associated with increased morbidity and mortality in more stable patients. Questions have also been raised as to the benefit of prophylactic (most transfusions) versus therapeutic platelet transfusions. Additionally, while red blood cells are being transfused to bring oxygen to tissues in need, and platelets are transfused to prevent/reduce further bleeding, their effectiveness in doing so is not known since often not measurable- hemoglobin levels or platelet corrected count increments are non-sensitive and inadequate effectiveness surrogates. Personalized blood cellular products derived from hematopoietic precursors or resulting from the implementation of novel processing and storage technologies could result in next generation cellular therapeutics that could potentially be used in smaller quantities; deliver specific therapeutics where needed; be effective (e.g., oxygenate hypoxemic tissues); be pathogen-free, less immunogenic, and free of potentially harmful plasticizers; and be available especially in times of emergencies.

Feasibility and challenges of addressing this CQ or CC :

Progress has been made in the last decade in producing blood products from stem cells, including gene-engineered cells. It is now possible to produce red blood cells and platelets from stem cells although the efficiency is low and the safety and efficacy of such products need assessment. New processing (e.g., pathogen-reduction) and storage (e.g. cold storage for platelets, new storage plastic bags) technologies are being considered although progress has been hampered by a lack of financial incentives and regulatory hurdles.

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Goal 3: Advance Translational Research

Develop Targeted Therapeutics to Treat Venous Thrombosis and Inflammation in Venous Thromboembolism

Venous Thromboembolism (VTE) afflicts nearly a million Americans yearly, has a mortality of 6-12% and has costs of more than $15 billion. Current treatment regimens, systemic anticoagulation and compression stockings, fail patients in multiple ways: risk of major bleeding episodes; failure of clot resolution in up to 50% of patients; failure to prevent the development of post-thrombotic syndrome (PTS) in up to 40% of ...more »

Submitted by (@chanduvem)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Venous Thromboembolism (VTE) is a common disease with established treatment regimens that have been repeatedly proven to fail patients. The disease process affects a million Americans, and projections are that this will increase to 1.82 million by 2050. VTE affects a wide range of the U.S. population including young pregnant women, cancer patients ,hospitalized patients and the ever expanding elderly sector. Despite recent advances the incidence of the disease is unchanged and treatment failures include failure to resolve clot, failure to prevent long-term recurrence and failure to treat vein wall inflammation which results in the development of post-thrombotic syndrome (PTS) in up to 40% of patients. There are significant complications from the approved systemic treatment regimens including bleeding from anticoagulation therapy and potentially fatal complications from inferior vena cava filters. In cases of severe chronic venous insufficiency (CVI), a common sequela of VTE, quality of life survey results mirror those of chronic lung disease, coronary disease and debilitating arthritis. The cost of VTE is nearly $15.5 billion in the U.S. alone. PTS significantly affects patients and up to 42% of patients lose workdays with a cost per patient of $11,667 and a cost to the overall system of $16 billion. Addressing this critical challenge will help to decrease mortality and morbidity in a large, active sector of the U.S. population and save the healthcare system billions.

Feasibility and challenges of addressing this CQ or CC :

This critical challenge comes at an opportune time as multiple platforms for targeted therapies have been tested, proven to be efficacious and nearing approval for use in patients. Basic science research in venous thrombosis has advanced significantly with well established in-vitro and in-vivo models. Furthermore, significant work has been done to reveal multiple targets for clot resolution and for the treatment of vein wall inflammation. Thus the critical information is known and therapeutics available to make addressing this challenge highly feasible.

There will be challenges to addressing this clinical need. The first challenge may be developing and/or identifying the most relevant animal model. There are multiple established animal models and these may need to be modified to provide the best simulation of the clinical situation being addressed. Secondly, there are multiple delivery platforms that would be suitable to this project including nanomedicine based therapies. These would have to be optimized and tested in this research realm and then would need FDA approval . Lastly, following pre-clinical studies it will take large scale clinical studies to prove the efficacy and then require re-education to adopt this approach in the treatment of patients with thrombosis. Fortunately understanding and addressing these challenges will ultimately result in an improved therapy for patients with venous thromboembolism.

Name of idea submitter and other team members who worked on this idea : Chandu Vemuri

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Goal 3: Advance Translational Research

Translational research supporting stem cell therapy for cardiovascular disease

Translational research supporting stem cell therapy for cardiovascular disease, including: core laboratories for preclinical IND-enabling studies (e.g., PACT), and clinical trials networks for evaluating promising new treatments (e.g., CCTRN).

Submitted by (@judith.l.bettencourt)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The most cost effective scientific procedure ever utilized to answer the risk benefit question posed by a new intervention to be used in humans is a clinical trial. Major clinical trials are their most effective when planted in controversial ground (MRFIT, CAST, ALLHAT). Like these studies, which were caught in a controversial dynamic of uncertainties and disparate sets of expectations, a clinical trial network to assess cell therapy is precisely what is needed.

Experienced researchers recognize the current inimical environment of cell therapy. Now - as before - some forces argue that new therapy offers no benefits, while other equally vehement constituents contend that the benefits of therapy are so great, and the risks so small, that the treatment requires little if any regulation and should be available at once to the US public. Each side provides thunder, but little light.

It is precisely in this contentious environment where passions argue beyond the data that clinical trials are required. Their construction of the most objective view of the strengths and weaknesses of the intervention comes at a cost, but the answers these well designed and concordantly executed studies provide is the clearest illuminations of the benefits and risks of human cell therapy.

Feasibility and challenges of addressing this CQ or CC :

Based on the unmet clinical needs in the treatment of cardiovascular disease and the compelling early evidence for the promise of cell therapy, NHLBI created the Cardiovascular Cell Therapy Research Network in 2007. Now in its ninth year, the Network has completed three major clinical trials in cell therapy. It has published 35 manuscripts in prestigious clinical journals including JAMA, Circ, and Circ Research. Its biorepository has published two manuscripts relating baseline phenotype findings to measures of left ventricular function. A fourth clinical trial is underway assessing the effect of cell therapy on peripheral vascular disease. The Network is also proceeding with the largest effort to assess the effect of CSC cells in patients with heart failure - the first clinical trial that will assess the effect of combined cell therapy in heart failure patients. In addition, CCTRN will study the effect of allogeneic mesenchymal stem cells in patients with anthracycline-induced cardiomyopathy. Each of these protocols is NHLBI and FDA approved.

CCTRN’s reputation of conducting and then promulgating the results of high quality clinical trials makes it the most effective mechanism to assess the benefits of cell therapy in cardiovascular disease. It is important to continue to fund the infrastructure already in place to ensure its continued high quality operation and its place as the cornerstone of cardiovascular clinical cell therapy research in the United States.

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