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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-33 net votes
10 up votes
43 down votes
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Goal 1: Promote Human Health

Stem cell niche in the lung

How do lung progenitors recognize stem cell niches, and what cell-cell interactions mediate normal repair?

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 :

Research on the stem cell-niche interaction will enhance our understanding of stem cell behavior, enable manipulation of stem cell activity and differentiation potential, and facilitate the development of stem cell-based therapy.

Feasibility and challenges of addressing this CQ or CC :

Developing novel models for in vitro 3D culture and in vivo transplantation assays will facilitate the progress.

 

Recent advances have identified and characterized several lung progenitor cell types. However research gaps remain on understanding the interaction of stem cells with the niche, and how the microenvironment impacts on the stem cell activity during injury/repair.

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

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8 net votes
23 up votes
15 down votes
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Goal 3: Advance Translational Research

Dissemination & Implementation of new treatments and therapies in sickle cell disease

Are current advances in gene editing, new drug therapies and less restrictive BMT criteria being explained and rolled out to the sickle cell community in an effective and timely manner? When can people living with sickle cell disease experience a better quality of life on more permanent based on the treatments we already have?

Submitted by (@sicklecellwarrior)

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

Details on the impact of addressing this CQ or CC :

Bone marrow transplant criteria has become less restrictive yet there has not been a steep increase in procedures. My understanding is that a sibling or child with the trait can be a donor. At some point this treatment needs to become more widely accessible and discussed with all patients by their doctors.

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc.

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46 net votes
55 up votes
9 down votes
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Goal 3: Advance Translational Research

Bone Marrow Stem Cell Transplant in Peds sibling matched SCD

There is a need to improve accessibility of Bone Marrow Stem Cell Transplantation (BMSCT) for Sickle Cell Disease patients who are most likely to benefit from this treatment option. 1. Building a culture of trust between and among primary care providers, specialists, patients/families, and other stakeholders 2. Consensus building around BMSCT as an acceptable treatment alternative (as opposed to another research endeavor) ...more »

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 :

1. It could potentially decrease the prevalence of SCD and significantly decrease the overall morbidity and mortality associated with SCD in children with matched sibling donors.

2. It could increase the awareness of health professionals who have a low awareness of the role of BMSCT in the treatment and cure of SCD (i.e., those in rural areas)

3. It can improve patient/family access to information and communications to facilitate informed discussion and choice for all SCD treatment options

4. It could open the gateway for more therapeutic applications for other genetic diseases

Feasibility and challenges of addressing this CQ or CC :

1. The science in this has evolved substantially such that BMSCT is a viable therapeutic option with reduced morbidity and mortality in the sibling matched population

2. There is an opportunity to broaden current collaborations with other agencies and the BMSCT community to expand the accessibility of their research forward.

3. Other agencies are emphasizing work in the area of BMSCT particularly for hemoglobinopathies.

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

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52 net votes
80 up votes
28 down votes
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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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32 net votes
52 up votes
20 down votes
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Goal 4: Develop Workforce and Resources

Sickle cell education for healthcare providers

Although sickle cell was first described more than 100 years ago and more than 100,000 individuals in the US are living with sickle cell disease, healthcare providers still lack basic knowledge of the key components in providing care for individuals with sickle cell. This often leads to poor health outcomes including stigmatization of patients with sickle cell seeking care. Evidenced-based curriculum should be available ...more »

Submitted by (@coretta.jenerette)

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 : International Association of Sickle Cell Nurses and Physician Assistants, Inc.

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18 net votes
21 up votes
3 down votes
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Goal 3: Advance Translational Research

Implementation science research to reduce adverse effects of SCD

From various publications and reports, we have characterized the risks associated with sickle cell disease (SCD) and understand many of the barriers for treatment of SCD in LMICs. How can implementation science research be used to reduce the negative outcomes of SCD in low/middle income countries?

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 :

• Reduction of deaths and negative outcomes associated with SCD and in LMICs

• Provide the evidence base that supports culturally relevant implementation strategies that reduce deaths associated with SCD in LIMCs

Feasibility and challenges of addressing this CQ or CC :

• Yes

, this is feasible

• Common goals and deliverables between NHLBI and partners will need to be identified

• Partnerships can be with international organizations, Ministries of Health and other partners

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

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18 net votes
31 up votes
13 down votes
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Goal 2: Reduce Human Disease

A Chidren's Oncology Group (COG) for sickle cell disease (SCD)?

We have all witnessed the success of the National Cancer Institute (NCI) funded Children's Oncology Group - an organization that has made tremendous advancements in the care of children with cancer, very rare compared to sickle cell disease. COG has been able to not only create a database of the numerous studies, but has the unique ability to make "smaller" institutions feel important as is evident by patient enrollment. ...more »

Submitted by (@smajumdar)

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

Details on the impact of addressing this CQ or CC :

- A database of all ongoing studies related to sickle cell disease that will be easily accessible by all pediatric hematologists

- A unified system of enrolling patients from academic centers for all the different studies, no matter how big or small

- Studies can be grouped depending on condition - renal disease, pulmonary hypertension etc.

- Should allow greater involvement/recruitment for patients into phase 1 studies

Name of idea submitter and other team members who worked on this idea : Suvankar Majumdar MD

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23 net votes
28 up votes
5 down votes
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Goal 3: Advance Translational Research

psychosocial care in sickle cell disease

What are the most effective trans-disciplinary and multi-level strategies for accelerating psychosocial care with sickle cell disease and how psychosocial factors impact families?

Submitted by (@sicklecellwarrior)

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

Details on the impact of addressing this CQ or CC :

Since sickle cell has multiple layers in medical treatment strategies, how can the same thought process happen when it comes to psychosocial matters? How can the NHLBI develop effective patient engagement trans-disciplinary and multi-level strategies that work with medical strategies to deal with psychosocial matters for individuals and families?

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc community members

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38 net votes
46 up votes
8 down votes
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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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115 net votes
149 up votes
34 down votes
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Goal 2: Reduce Human Disease

Impact of each VOC Crisis in patients with sickle cell disease

While the long term cumulative effects of frequency, duration and severity of VOC on mortality is known in SCD, there is little known about the impact of each individual crisis or the amount of damage during crisis versus background smoldering ischemia from the disease. Any effort in quantifying this for SCD in the absence of interventional agents initially, and then as a potential measurement of the benefit of drug ...more »

Submitted by (@tosinola)

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

Details on the impact of addressing this CQ or CC :

This may help science inform additional treatment options for sickle cell disease, and serve as a cornerstone for further research particularly in the realms of drug development that addresses individual components of a sickle cell crisis.

Feasibility and challenges of addressing this CQ or CC :

This is feasible but has not been chosen as a research prerogative. A challenge is that there is no current way to measure what happens internally during a VOC.

Name of idea submitter and other team members who worked on this idea : Tosin Ola, Greg Gorgas

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3 net votes
3 up votes
0 down votes
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Goal 2: Reduce Human Disease

Sickle Cell anemia and Aplastic anemia survivors: Late effects and quality of life issues in Stem Cell Transplant Survivors

Most of the patients suffering from non-malignant hematologic conditions are cured of the original disease with Hematopoitec Stem Cell Transplant (HSCT) but still their survival is less compared to age matched general population, and additionally they suffer from unique complications of HSCT culminating into a variety of late physical, psychologic, financial, and social complications (“late effects”). Considerable improvements ...more »

Submitted by (@hashmi.shahrukh)

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

Details on the impact of addressing this CQ or CC :

One million HSCT mile stone was recently reached and the utilization of HSCTs continues to increase. For many non-malignant hematologic conditions particularly sickle cell anemia and bone marrow failure syndromes, HSCT is the only potentially curative option. Most HSCT survivors are living beyond a year, but can suffer from devastating complications of HSCT which include graft-versus-host-disease, second cancers, diabetes, infertility, congestive heart failure, blindness, and bronchiolitis obliterans, besides many others which lead to increased overall HSCT related disease burden. A lot of efforts are currently being put in cancer survivorship by the ACS, NCI, ASCO and other societies, but very little emphasis is being laid on sickle cell or aplastic anemia survivors. This area of HSCT survivorship becomes more important from health disparities perspective too, since majority of the hemoglobinopathy HSCTs performed in the US are in racial minorities. Comparative effectiveness research (CER) in HSCT survivorship is essential to delineate the overall disease burden this population and understand the risks and outcomes of HSCT late effects. To compare the effectiveness of survivorship programs and research, especially for those survivors who are at risk of health disparities is a top priority of the Institute of Medicine CER 2009 initiative.

Feasibility and challenges of addressing this CQ or CC :

Majority of the HSCT survivors of benign hematologic conditions are now living beyond 2 years post-HSCT. Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) was established in 2001 to conduct large Multi-Institutional clinical trials and is funded by the NHLBI. Since the infrastructure is in place to conduct studies related to all aspects of HSCT, this would be an area to explore first from feasibility perspective since thousands of patients have already been successfully enrolled through the BMT-CTN studies. From NHLBI strategic perspective, this would place CTN (and Emmes Corporation) in an excellent unique position of addressing CER for survivorship issues and health disparities within one study, since the population understudy would mainly be consistent of racial minorities – with the overall goal of improving the long term health, preventing late effects, improving quality of life, and reduce the overall health burden (DALYs and societal costs) of thousands of HSCT survivors in the US and globally.

Name of idea submitter and other team members who worked on this idea : Shahrukh Hashmi

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71 net votes
89 up votes
18 down votes
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