Goal 1: Promote Human Health

Promoting the Development of Animal and Cellular Model Systems

NHLBI might consider creating incentives for the development of core labs and national facilities to promote development of animal and cellular model systems that mimic lung injury, repair, and regeneration.

Submitted by (@skrenrich)

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 : Cystic Fibrosis Foundation

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Goal 3: Advance Translational Research

Overcoming barriers to translational regenerative medicine

Current stem cell based approaches to translational medicine predominantly show modest efficacy. Most research rest on accepting existing limitations and focusing upon "tweaks" to the experimental model rather than taking on important barriers head on. The efficacy of stem cell-based regenerative medicine will never be fully realized unless we stop trying overly simplistic approaches such as"more is better" and start ...more »

Submitted by (@heartman4ever)

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 field of regenerative medicine holds great potential but we risk losing the public trust by hyperbolic promises, modest efficacy, and incremental research steps. Truly innovative research will transform the landscape and offer truly novel therapeutic approaches to many current incurable conditions. The result is a dramatic shift in the practice of medicine, new options for treatment, enhanced engagement of the public in biomedical research and new growth opportunities for the NIH and biotech sectors.

Feasibility and challenges of addressing this CQ or CC :

The future is here for regenerative medicine, but for the most part the potential and practice has been unrealized or poorly executed. The challenge is to identify the limiting factors and sweep them aside. There is broad and surprisingly consistent consensus on what the barriers are to successful regenerative therapy, but it seems most researchers are complacent and accept these limitations as inherent in the system rather than try to find truly combative approaches to overcome the barriers to enhancing regenerative processes. So it is essential to change the current mindset and push for a full frontal attack on the barriers that impede successful regeneration rather than minor modifications or uninspired brute force approaches that ignore the underlying mechanistic issues. Also, a major challenge is the hyperbole and overselling of research findings and impact by researchers and their institutions looking to capitalize upon the "discovery de jour." Such overly optimistic and unrealistic promises undermine our position in the public eye and compromise our future ability to earn the public trust.

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

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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 1: Promote Human Health

Funding of Stem Cell/Lung Regeneration Research

How to "cure" a chronic, incurable disease - A potential giant step in saving the lives of many thousands of Americans, and potentially millions worldwide, who are afflicted with COPD, the third leading cause of death in the U.S. The financial effect of COPD in the United States alone is well over $50 billion per year. It is estimated that some 30 million Americans have COPD, which of course means that at least that ...more »

Submitted by (@jimandmarynelson)

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

Details on the impact of addressing this CQ or CC :

COPD is chronic and presently incurable. Although it sickens and disables nearly 30 million Americans, and kills 140,000 of them each year, the only "cure" is a lung transplant. Due to the scarcity of organ donors and the requirements that lungs be removed from the donor in a hospital setting, only about 1,400 lung transplants are performed in the Unites States each year. Unfortunately, transplants are fraught with complications, side effects, and potential rejections, and on the average, add only about 5 years to the life of the recipient. The best potential solution lies with the stem cell and lung regeneration research that is presently occurring at a few centers around the country. Ideally, the re-engineered lungs would be composed of the patient's own stem cells, eliminating a great many of the current transplant issues.

Feasibility and challenges of addressing this CQ or CC :

Research is presently in process on construction or reconstruction of human organs. There has been success in creating some of the simpler organs, such as the esophagus and bladder, and a Medical Center in Galveston has implanted re-engineered lung is a pig. As of my latest conversation with the lead Doctor on the project, results so far are promising.

There is general agreement among the researchers with whom I have communicated that we are between 5 and 20 years away from human trials of re-generated lungs using the patient's own stem cells, but more funding means more research which means more possibilities of the saving of lives.

Name of idea submitter and other team members who worked on this idea : Jim Nelson - COPD Foundation MASAC/CAC/BOARD Committee Member

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Goal 1: Promote Human Health

Injury, regeneration and repair of the developing lung

Understanding injury, regeneration and repair of the developing lung.

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

While we are fully supportive of the recent emphasis on patient‐centered outcomes and implementation science, we are also reminded of the critical importance of investigating underlying mechanisms of pulmonary, critical care and sleep disorders. Recent discoveries have created exciting progress in the areas of cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and biological therapies in asthma. Only through further efforts to elucidate underlying mechanisms are new therapeutic approaches likely to emerge. Promoting further academic‐industry interactions are likely to yield benefits, which will ultimately lead to improvements in the health of our nation.

Name of idea submitter and other team members who worked on this idea : Research Advocacy Committee, American Thoracic Society

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Goal 2: Reduce Human Disease

Regeneration of Failing Heart while Resting on Left Ventricular Assist Device

Heart transplant is the ultimate treatment for AHA stage-D heart failure. Due to availability, heart transplants will be limited to about 2,500 per year. Patients with AHA stage-D heart failure has estimated prevalence of 0.2% for age >45. Thus, patients in need far exceed organs available. A failed heart has very challenging environment for cellular therapy. Left ventricular assist device (LVAD) can offload the heart ...more »

Submitted by (@ctong0)

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 : Carl Tong

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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)

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

Details on the impact of addressing this CQ or CC :

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 3: Advance Translational Research

Embedding the future of regenerative medicine into the open epigenomic landscape of pluripotent human embryonic stem cells

Large-scale profiling of developmental regulators and histone modifications by genome-wide approaches have provided powerful genome-wide, high-throughput, and high resolution techniques that lead to great advances in our understanding of the global phenomena of human developmental processes. However, without a practical strategy to convert pluripotent cells direct into a specific lineage, previous studies are limited ...more »

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 :

Large-scale profiling of developmental regulators and histone modifications by genome-wide approaches have provided powerful genome-wide, high-throughput, and high resolution techniques that lead to great advances in our understanding of the global phenomena of human developmental processes. However, without a practical strategy to convert pluripotent cells direct into a specific lineage, previous studies are limited to profiling of pluripotent human embryonic stem cell (hESC) differentiating multi-lineage aggregates, such as embryoid body that contain mixed cell types of endoderm, mesoderm, and ectoderm cells or a heterogeneous population of embryoid body-derived cardiac cells that contain mixed cell types of cardiomyocytes, smooth muscle cells, and endothelial cells. Their findings have been limited to a small group of genes that have been identified previously in non-human systems, and thus, have not uncovered any new regulatory pathways unique to human development. Although genome-wide mapping of histone modifications and chromatin-associated proteins have already begun to reveal the mechanisms in mouse ESC differentiation, similar studies in hESC are currently lacking due to the difficulty of conventional multi-lineage differentiation approaches in obtaining the large number of purified cells, particularly cardiomyocytes, typically required for ChIP-seq experiments.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent technology breakthrough in lineage-specific differentiation of pluripotent hESC by small molecule direct induction allows generation of homogeneous populations of neural or cardiac cells direct from hESC without going through the multi-lineage embryoid body stage. This novel small molecule direct induction approach renders a cascade of neural or cardiac lineage-specific progression directly from the pluripotent state of hESC, providing much-needed in vitro model systems for investigating the genetic and epigenetic programs governing the human embryonic CNS or heart formation. Such in vitro hESC model systems enable direct generation of large numbers of high purity hESC neuronal or cardiomyocyte derivatives required for genome-wide (e.g., ChIP-seq) profiling to reveal the mechanisms responsible for regulating the patterns of gene expression in hESC neuronal or cardiomyocyte specification. It opens the door for further characterizing, identifying, and validating functional elements during human embryonic development in a comprehensive manner. Further using genome-wide approaches to study hESC models of human heart formation will not only provide missing knowledge regarding molecular cardiogenesis in human embryonic development, but also facilitate rapid progress on identification of molecular and genetic therapeutic targets for the prevention and treatment of cardiovascular disease.

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

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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 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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