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)

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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.

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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

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)

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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

Translational Cardiovascular Medicine

There is a need for the NHLBI to catalyze the development of tools and shared data resources to facilitate mechanistic studies in a human model system. This includes the ability to culture human cardiac tissue, as well as generate a resource to systematically characterize and catalog the epigenome and histone marks associated with the transcriptome in normal and diseased heart tissues.

Submitted by (@stacey.rentschler)

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The in-depth characterization of complex cellular systems is often beyond the scope and capability of individual investigators working in isolation. The NHLBI research community lacks a shared tissue-specific systems biology framework resource that would accelerate the progress of individual, investigator-initiated research.

 

The Human Genome Project and subsequent sequencing projects are characterizing the structural architecture of the human genome, but the biological significance of the human genome and the characterization of functional elements that mediate gene-environment interactions and influence tissue-specific gene expression remain to be further defined.

Feasibility and challenges of addressing this CQ or CC :

Advances in the ability to culture adult human cardiac tissue for prolonged periods while maintaining normal electrical and mechanical function will enable testing of novel therapeutics to treat cardiovascular disease. Tissue-specific epigenetic modification of nucleic acids and dynamic changes in the histone code and chromatin remodeling are important determinants of the transcriptome within heart tissue. Advances in the ability to perform genome-wide analyses in human cardiac tissues to assess dynamic changes in the histone code and chromatin remodeling will enable comparison between normal and disease states.

Name of idea submitter and other team members who worked on this idea : Stacey Rentschler and colleagues, Washington University in St. Louis

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Goal 3: Advance Translational Research

Current State of Regenerative Medicine: Moving Stem Cell Research from Animals into Humans for Clinical Trials

Realizing the developmental and therapeutic potential of pluripotent human embryonic stem cell (hESC) derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation.

Submitted by (@xuejunparsons)

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Realizing the developmental and therapeutic potential of pluripotent human embryonic stem cell (hESC) derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient, incomplete, and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. In addition, undefined foreign or animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for derivation and maintenance of clinical-grade pluripotent hESC and lineage-specific differentiation of pluripotent hESC by small molecule induction. Such milestone advances and medical innovations in hESC research enable direct conversion of pluripotent hESC into a large supply of homogeneous populations of clinical-grade hESC neuronal and heart cell therapy products for developing safe and effective stem cell therapies. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and 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 1: Promote Human Health

The Human Virome and Host Interactions in Heart, Lung, and Blood

What are the unknown elements of the human virome, and what host-virome interactions affect the heart, lung, and blood health and diseases? A major challenge has been the need for in vitro culture systems and animal models for studying the virome, which is a significant limitation that has forced current studies of the virome to be mostly descriptive. NHLBI has supported one research group to identify human virome and ...more »

Submitted by (@nhlbiforumadministrator)

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• The virome contains the most abundant and fastest mutating genetic elements on Earth. The human virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. The virome may influence the host in profound ways independent of classical viral disease. The immune system is continuously stimulated by chronic systemic viruses and this aspect of host-microbiome interactions appears specific to the virome. The virome is considered one of the drivers of idiopathic systemic inflammation that has been linked to many of the most severe public health threats, including cardiovascular diseases. Disruptions in immunity by immunosuppressing events can undoubtedly alter the interactions of the virome with the host. However, little research has been done in all of these aspects other than limited descriptive studies to identify the presence or composition of the human virome. The NHLBI Microbiome Working Group in June 2014 clearly identified under-representation of studies of the human virome. Identification and characterization of unknown viral elements of the human virome and research on the interactions with the host will allow exploration of their impact on heart, lung and blood health and diseases, including impact in the presence of immunosuppression with the host such as in AIDS or HIV infection.

Feasibility and challenges of addressing this CQ or CC :

This initiative is feasible because of new technologies that have been developed recently such as the deep sequencing techniques. The initiative is also timely in that research supported by the NIH Human Microbiome Program and other programs has allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the virome. This initiative will attract more investigators to not only identify more elements of the virome but more importantly to understand the roles of the human virome in heart, lung and blood health and diseases, and eventually to help develop diagnostic and intervention strategies.

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

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Goal 4: Develop Workforce and Resources

Preserving and promoting expertise in integrative physiology

From my perspective, one of the key “critical challenges” facing the NHLBI in particular, and medical science in general, is to avoid being blinded by the promises of the reductionists in the “personalized, precision medicine” of the future. In order to understand the advances being made at the molecular level, we need to preserve and promote expertise in truly integrative physiology, what I like to call “PHYSIOMICS”. ...more »

Submitted by (@nhlbiforumadministrator)

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Unfortunately, human physiologists are being squeezed out of the medical industrial complex by the basic scientists on one end, and the epidemiologists on the other. Most departments of medicine now require on 80/20 commitment to have a significant research component of an academic career, and it is becoming increasingly difficult for those few of us physiologists remaining to compete with the pressures of both research funding and clinical mandates. I urge the leadership at NHLBI to preserve a strong focus on human physiology, and continue to support the small, but high resolution studies that are required to answer key research questions. I would submit that studying an individual patient’s unique physiology is as much “personalized” or “precision” medicine as it is to read their genome. Remember, despite billions of dollars of research support, there remains nothing better to predict the risk of diabetes, than a simple measure of waist size!

Name of idea submitter and other team members who worked on this idea : Benjamin Levine

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Goal 2: Reduce Human Disease

International collaboration for genetic and metabolic research on specific human population

During recent years, clinical research including well-organized randomized clinical trials in developed countries generated large database and human biological sample banks. These are valuable resources for human disease research. Mechanisms to encourage and facilitate international collaboration for genetic and metabolic research using database and human biological samples from specific human disease population of international ...more »

Submitted by (@hongw0)

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

Name of idea submitter and other team members who worked on this idea : Hong Wang, Xiaofeng Yang

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Goal 3: Advance Translational Research

Better disease models

Many diseases of the heart, lung and blood systems are studied using animal models, often with genetically engineered mice. However, while mice get models, humans get diseases. Too many grants are devoted to curing models, a practice encouraged by many high profile journals who want to see “proof” in a standard model of disease. Much less time, effort and money will be wasted on developing ineffective therapies if focus ...more »

Submitted by (@nhlbiforumadministrator)

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Morphologic appearance is necessary but insufficient as a criterion for validating a model. Comparative “omics” should be strongly encouraged. It is a waste of resources to develop therapies based on the effects of yet another gene knock out in something as unphysiological as atherosclerotic lesions in an ApoE knock out mouse or asthma in a mouse with eosinophilic airspace disease that largely ignores the bronchial tree or the infusion “stem cells” on cardiac function in a mouse with an experimental myocardial infarct. These are simply prominent examples of widely used standard models with little real utility. Therapies based on such approaches are likely to fail. Better models that more realistically capture phenotypic features of real diseases could lead to more promising therapies.

Feasibility and challenges of addressing this CQ or CC :

Model development is not very sexy and stands a better chance of acquiring support outside the standard study section review mechanism where proposals are judged by investigators with a vested interest in (and academic career based on) using existing models, despite their poor track records.

Name of idea submitter and other team members who worked on this idea : Jordan S. Pober

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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)

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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 1: Promote Human Health

Mechanism of dietary polysaccharide/ sugars in averting CVD and cancer

CQ

Submitted by (@mayaraman)

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Non-communicable diseases and their preventive measure are always of interest. But we always, face side-effects because of these new applications. And at times, these techniques fail.

Diet today is a attractive area of discussion. Everyday, we read or hear that control of diet has cured severe conditions.

In fact, as the saying goes, we are what we eat. Today, scientific communities can lay emphasis on the researches concerning these topics. Dietary polysaccharides/ polyphenols etc. have a promising role in deciding our health. We can include these in our diet but the mechanism of the action of these factors in preventing diseases has not be explored in detail. The role of specific factors in diet at specific sites, may assist in pin-point treatment with better results and no side-effects. Can this topic be considered for research!

Feasibility and challenges of addressing this CQ or CC :

Challenges include creating teams of researchers with basic research expertise and experienced researchers to collaborate and come up with plans to understand the action of system and to design strategies utilizing dietary carbohydrates to have healthier and long term benefits.

Name of idea submitter and other team members who worked on this idea : Raman M

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Goal 3: Advance Translational Research

Infrastructure for human translational research

With the reduction in NCAT support for human translational research, infrastructure support will need to come from the NHLBI. This will increase the cost of most human, mechanistic based RO1 studies by 20-30%. This will exceed the current cap of $500K in many circumstances. The cap will need to be raised or NHLBI and other institutes need to determine how NIH can continue to provide this critical infrastructure.

Submitted by (@gwilliams)

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

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With the pending loss of infrastructure support by NCAT for human translational, mechanistic studies, a contiued decline in resources to support this critical resources for N of 1 studies. With appropriate support there will be increased capacity to determine which pre-clinical data is applicable to humans and to design more percise, mechanism based clinical trials to increase the likelihood of precision, personalized medicine for many of NHLBI's targeted diseases, e.g, hypertension, stroke, cardiovascular disease with diabetes and hypertension, asthma, and sleep apnea.

Feasibility and challenges of addressing this CQ or CC :

The template for addressing this challenge is already available. The specific funding mechanism(s) will need to be addressed.

Name of idea submitter and other team members who worked on this idea : Gordon Williams, Gail Adler, Charles Czeisler, Ellen Seely, Lindsey Baden

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Goal 3: Advance Translational Research

The Investigator's Catch-22: How Can NHLBI Help?

The Critical Challenge is to determine how NHLBI can continue to foster the translational research necessary to allow our researchers to further develop their NHLBI-funded basic science discoveries. Researchers can't readily get a "typical" grant to perform the preclinical and early clinical translational IND-enabling research, and also can't yet attract private sector support without having done the work to "de-risk" ...more »

Submitted by (@nhlbiforumadministrator1)

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Ensuring that NHLBI-funded researchers have the means to further develop promising research discoveries will ensure that NHLBI continues to fulfill its Mission. Providing funding or resources to move basic science discoveries from the lab towards the clinic can expand the research environments, opportunities, and collaborations available to NHLBI investigators and lead to potential new therapies for heart, lung, and blood diseases.

Feasibility and challenges of addressing this CQ or CC :

Just as research project itself can take years, if not decades, to accomplish, so too can a cultural shift in our extramural research community. While one may have a different understanding of what constitutes "translational" research depending upon his or her vantage point, in reality it is bi-directional (from bench to bedside and back to bench) and offers possibilities for a wide range of researchers. Engaging established basic scientists in translational research can open new opportunities to them, and younger researchers are likely more familiar and well-poised for new research paradigms and collaborative efforts such as those afforded by the translational development process.

Basic discovery science is appropriately the backbone of the NHLBI extramural research program. But, for any basic science discovery to have a meaningful impact on human health, it must be "translated from the bench to the bedside." These next steps in translation involve a tremendous amount of research that is not amenable to hypothesis-driven grant mechanisms like an R01 or P01. Without access to funding support for early-stage translational work, investigators can be stymied and NHLBI-funded basic science discoveries can languish.

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

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