Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

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

Details on the impact of addressing this CQ or CC :

Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

Voting

7 net votes
11 up votes
4 down votes
Active

Goal 2: Reduce Human Disease

How can we non-invasively, but still accurately, measure blood pressure in the pulmonary arteries?

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. The gold standard for measuring pressures in the pulmonary arteries is a right heart catheterization, where a special catheter is guided through the right side of the heart and into the pulmonary artery, the main vessel carrying blood to the lungs. This measurement is essential, as it allows physicians and ...more »

Submitted by (@katherinek)

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

Details on the impact of addressing this CQ or CC :

i. In patients with pulmonary hypertension, the use of multiple tests to characterize the type and severity has long been recommended by global experts; one commonly used diagnostic algorithm recommends more than ten different tests to accurately define this complex, heterogeneous disease. Despite the algorithm used, to confirm a diagnosis of one specific type of PH, pulmonary arterial hypertension (PAH), one must always directly measure the pressures in the heart and pulmonary artery through a right heart catheterization (RHC). Complications for this procedure are rare, but not non-existent with potentially 1 in every 100 patients having a right heart catheterization experiencing a serious adverse event (Hoeper MM 2006). Patients would significantly benefit from a non-invasive method of quantifying their pulmonary artery pressures and/or disease progression, but to date this has not been possible with echocardiography due to measurement errors (Laver 2014), CT scan due in part to measurement inconsistencies (Alhamad 2011), and cardiac MRI due to lack of standardization and multicenter trials (Peacock 2013). Not only would wider utilization of a non-invasive method of measuring pulmonary artery pressures and disease progression potentially reduce the risk from RHC, depending on the modality it could lead to earlier diagnosis of this progressive disease and/or application in countries where RHC is less common.

Feasibility and challenges of addressing this CQ or CC :

Addressing a non-invasive method of measuring pulmonary artery pressures requires investment in both technology and multicenter clinical trials to validate these measures.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

Voting

67 net votes
75 up votes
8 down votes
Active

Goal 2: Reduce Human Disease

Biomarkers of Pulmonary Hypertension

What are informative and clinically relevant biomarkers of pulmonary hypertension (PH)?

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 :

This research emphasis would help identify novel pulmonary hypertension biomarkers of disease risk and progression that can be used for early detection or as outcome measures in prevention trials or treatment of PH, which is a disease currently still not curable with high mortality rate.

Feasibility and challenges of addressing this CQ or CC :

NHLBI Division of Lung Diseases just launched the multi-center PVDOMICS research program last September that will enroll ~1,500 patients in the next 5 years for deep phenotyping PH. PVDOMICS will provide a perfect foundation and platform for this proposed featured study about informative and clinically relevant biomarkers of PH, and make answering this proposed question more feasible in the next 5-10 years.

Although significant advances in the treatment of pulmonary hypertension have been made in the past two decades, currently pulmonary hypertension remains a devastating disease without many clinically relevant and specific biomarkers available. Novel new informative and clinically relevant pulmonary hypertension biomarkers would greatly help advance the subtype-specific early diagnosis and precision treatment of this disease that could potentially decrease the mortality of PH.

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

Voting

75 net votes
87 up votes
12 down votes
Active

Goal 2: Reduce Human Disease

Fibrosis Care Center Network and Patient Registry

Complex diseases such as interstitial lung disease and pulmonary fibrosis requires a collaborative effort to effectively characterize, appropriately diagnose, and efficient evaluate novel therapies. Similarly, basic, translational and clinical research in this field requires the integration of clinical phenotypes with biologic specimens. We propose the expanded development of the Care Center Network and Patient Registry ...more »

Submitted by (@gcosgrove)

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 envisioned impact of an integrated Care Center Network and Patient Registry is to create a resource that:

 

• Informs the understanding of interstitial lung disease (ILD), its epidemiology and natural history;

• Assists to understand treatment patterns associated with optimal outcomes that will inform an emerging standard of care and development of treatment guidelines;

• Facilitates patient and clinician engagement in support of future prospective studies;

• Furthers study of biomarkers and predictors of disease and severity;

• Documents patient experience of living with ILD as described through patient reported outcomes (PRO) including quality of life, functioning, and symptoms;

• Generates new hypotheses and new endpoints in support of future studies;

• Increases awareness of relevant issues and needs among the immediate ILD community;

• Provides the opportunity to promote and inform policies in the larger health care community in support of those with ILD

Feasibility and challenges of addressing this CQ or CC :

With the establishment of collaborations between several partners, we initiated the PFF Care Center Network and Patient Registry in 2014. The Care Center Network and Patient Registry has since expanded to 21 centers regionally dispersed throughout the United States. The challenges of effectively and efficiently investigating the cause, care and treatment of pulmonary fibrosis are predominantly those of organization and integration of effort. Expertise is present throughout the United States. We suggest that with the continued expansion of the Care Center Network and Patient Registry, those challenges will be overcome and the focus of the fibrosis community efforts can be on diligently investigating the diseases that devastatingly affect patients. An integrated repository of well-phenotyped patients and biologic specimens is the first step in Precision Medicine for patients with interstitial lung disease and pulmonary fibrosis.

Name of idea submitter and other team members who worked on this idea : Gregory P. Cosgrove, MD, The Pulmonary Fibrosis Foundation

Voting

2 net votes
2 up votes
0 down votes
Active

Goal 2: Reduce Human Disease

Optimization of Existing Therapies for Sickle Cell Disease

How can the safety, dosing and benefits of existing therapies for sickle cell disease such as hydroxyurea, be optimized in order to increase its efficacy and improve patient adherence?

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

Details on the impact of addressing this CQ or CC :

Hydroxyurea is a widely available disease-modifying therapy for sickle cell disease (SCD), but its effectiveness is currently limited by inadequate utilization, and less than optimal response. Research is needed to improve adherence to this evidence-based therapy and emphasis needs to be placed on determining whether therapy with hydroxyurea can prevent or even reverse organ dysfunction. In addition, research identifying new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease, and pulmonary hypertension will be valuable in the management and treatment of SCD.

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

Voting

54 net votes
74 up votes
20 down votes
Active

Goal 2: Reduce Human Disease

Challenge

Genetic or biologic makers that predict outcomes in pulmonary fibrosis are needed.

Validated animal models of lung fibrosis that better resemble the human condition are needed to speed up the drug development process.

An international patient registry is needed to help promote understanding of the natural history of pulmonary fibrosis and real-world impacts of interventions.

Submitted by (@swigrisj)

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

Voting

1 net vote
6 up votes
5 down votes
Active

Goal 2: Reduce Human Disease

Identification and validation of surrogate endpoints for long-term morbidity in Sickle Cell Disease

Research in sickle cell disease (SCD) has mostly focused on preventing or treating acute medical events, such as vaso-occlusive pain, acute chest syndrome, and, in pediatric patients, acute strokes. Chronic SCD complications such as chronic kidney disease or pulmonary hypertension, develop over decades, thus are poor choices for clinical trial endpoints. There is a great need to develop surrogate endpoints that predict ...more »

Submitted by (@hulbertm)

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

Details on the impact of addressing this CQ or CC :

Longitudinal cohorts of SCD patients, spanning childhood and adulthood, with biobanking DNA, plasma, and serum, and standardized clinical and imaging assessments will allow identification predictors of negative clinical outcomes. An NHLBI-funded national SCD clinical registry with biobanking will be necessary to validate any surrogate endpoints.

Name of idea submitter and other team members who worked on this idea : Monica Hulbert

Voting

13 net votes
16 up votes
3 down votes
Active

Goal 3: Advance Translational Research

Increasing Regenerative Medical Strategies in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Current PAH therapies mainly act of the vasoconstrictive component of the disease; however there is a widely accepted view that another contributor to the disease is an abnormal overgrowth of cells that line the pulmonary arteries, which ...more »

Submitted by (@michaelg)

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

Details on the impact of addressing this CQ or CC :

In the past twenty years, 12 PAH targeted-therapies have been approved by the FDA. This increase in disease state awareness and in the treatment armamentarium have contributed to an increase in average survival from 2.8 years to an estimated 8-10 years. However, current treatments primarily address the vasoconstrictive component of the disease and do not address the now accepted theory of post-apoptotic overgrowth of hyperproliferative cells of the pulmonary vessels. A number of circulating stem and progenitor cells, derived from the bone marrow, have been identified that could have roles in repair of the pulmonary vascular system when interacting with the quickly, abnormally growing cells in the lung vessels. Work in this area has been named as a future research opportunity in the NHLBI-ORDR Strategic Plan for Lung Vascular Research (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

Basic and translational research support is needed—including high-throughput approaches such as phage display and large-scale proteomic analysis—to better understand the relationship between circulating bone marrow-derived cells, lung-resident stem and progenitor cells, and endothelial cells of the pulmonary arterial system.

Name of idea submitter and other team members who worked on this idea : Pulmonary Hyeprtension Association, Michael Gray, Katie Kroner

Voting

71 net votes
81 up votes
10 down votes
Active

Goal 2: Reduce Human Disease

How can we better understand regional tissue heterogeneity in lung disease?

Many lung diseases (IPF, COPD) are characterized by marked heterogeneity at the tissue level. Unfortunately, most of the tools we currently employ to understand lung disease are unable to elucidate the mechanisms that result in regional heterogeneity. Clinical studies and animal models, while invaluable, generally assume that all lung tissue is similarly affected based on the presence or absence of diagnostic criteria ...more »

Submitted by (@bradley.richmond)

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

Details on the impact of addressing this CQ or CC :

Emerging evidence suggests that diseases such as IPF and COPD have observable phenotypes at the cellular and tissue levels long before the disease is clinically apparent. Thus seemingly healthy patients may have some regions of the lung affected by the same pathophysiologic processes that drive clinically apparent disease. By changing the focus of investigation from the presence or absence of disease in a given patient to the presence of absence of disease in a given region, several advantages emerge: (1) pathophysiologic mechanisms may be investigated earlier in the natural history of a disease, when interventions are more likely to be of benefit; (2) early investigation favors the discovery of distinct disease subgroups that are masked in more severe disease; and (3) a single patient may provide multiple affected and unaffected disease regions, allowing him or her to serve as their own control. Recently, advances in next-generation sequencing have made it possible for the entire transcriptome of a single cell to be analyzed. It is reasonable to believe that in the next 10 years single cell epigenome, proteome, and metabolome profiling will become routine. However, it seems less obvious how these methodologies can be employed to better understand the drivers of regional differences in lung disease. While technically difficult, studies applying high-throughput technologies to the discovery of regional differences will be invaluable to our understanding of lung disease.

Feasibility and challenges of addressing this CQ or CC :

To address this critical challenge, at least five technological hurdles will have to be addressed: (1) technologies such as laser capture microdissection which allow for the isolation or cells from specific areas of the lung will need to improve; (2) technologies allowing for culture of multiple cell types on a single artificial substrate (to allow for experimental manipulation of cellular “communities”) will need to emerge; (3) collaborative networks will need to emerge whereby datasets from multiple labs can be integrated; (4) bioinformatics and statistical methods capable of filtering massive “omics” data sets from multiple cell types will need to be refined; and (5) researchers with the skills necessary to distil large descriptive datasets into testable hypotheses will need to be trained. While these hurdles are great, they must be overcome in order to translate the promise of next-generation sequencing techniques into an improved understanding of the drivers of regional heterogeneity in lung disease.

Name of idea submitter and other team members who worked on this idea : Bradley Richmond

Voting

9 net votes
26 up votes
17 down votes
Active

Goal 2: Reduce Human Disease

What causes variation in severity of skeletal muscle, lung, pulmonary and heart system symptoms in FSHD muscular dystrophy

Loss of diaphragm function and impaired respiration is a leading driver of morbidity and mortality in the adult muscular dystrophies such as facioscapulohumeral muscular dystrophy, and therefore requires additional study

Submitted by (@daniel.perez)

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

Details on the impact of addressing this CQ or CC :

Muscular dystrophies comprise a heterogeneous group of genetic diseases often characterized by multi-systemic effects and distinct patterns of muscle involvement. While a characteristic pattern of muscle weakness has traditionally been used to define the different subtypes of muscular dystrophy, the cause for the regional distribution of muscle weakness, often with sparing of specific muscle groups, has largely remained unresolved. Moreover, many muscular dystrophies such as the most common form facioscapulohumeral muscular dystrophy, show noticeable variation in disease onset and progression, both between as well as within families. Involvement of the diaphragm and muscles of respiration often proceeds at a rate different from other striated muscles. Loss of diaphragm function and impaired respiration is a leading driver of morbidity and mortality in the muscle diseases, and therefore requires additional study in adult muscular dystrophy.

Feasibility and challenges of addressing this CQ or CC :

Studies in mice and humans have provided some evidence for genetic modifiers of disease onset, presentation and progression, but a comprehensive explanation for the observed differences in skeletal muscle, lung, pulmonary and heart system involvement and disease progression is currently lacking. Disease penetrance may be affected by genetic background or gene-environment interactions. Future studies on the identification and validation of such factors, both genetic and non-genetic (off target effects of drugs, diet, exercise), may provide insight into strategies that delay disease onset, prevent off-target effects of drugs and improve quality of life.

Name of idea submitter and other team members who worked on this idea : FSH Society

Voting

-10 net votes
6 up votes
16 down votes
Active

Goal 2: Reduce Human Disease

Would patients with pulmonary arterial hypertension (PAH) benefit from background anticoagulation in addition to their PAH-targe

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. For several decades, oral anticoagulation has been recommended by some societies for patients with a specific form of PH called pulmonary arterial hypertension. However, the evidence currently supporting this recommendation is very limited. To date, no prospective randomized clinical trial has been completed ...more »

Submitted by (@katherinek)

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 evolution of the anticoagulation recommendation in pulmonary arterial hypertension (PAH) is a relatively logical one at face value. Early in the modern era of PAH management, a “thrombosis” in the small pulmonary arteries was identified and described; studies since then have demonstrated hypercoagulability in patients with severe disease. Together, these observations led to a theory that in-situ thrombosis contributed to the PAH disease progression and a belief that anticoagulation should be beneficial. The empirical evidence currently supporting this recommendation comes mostly from a retrospective cohort study of the European COMPERA PH registry and a systematic review of 7 retrospective cohort studies that are at least 10 years old—2 of which did not suggest a survival benefit—and in a time where only 4 of the widely used PAH-targeted therapies were approved by the FDA. Purely based on observational evidence with a number of potential biases, warfarin (Coumadin) is widely used in PAH management to this day. Warfarin in this patient population is not without its risks, as some subgroups of PAH patients are at increased risk of bleeding complications based on their disease process alone. Assessing the true benefit of this widely used background therapy could allow clinicians and patients to more accurately weigh the risks and burden of anticoagulation with a true understanding of the survival benefit.

Feasibility and challenges of addressing this CQ or CC :

Addressing this compelling question is indeed feasible through an NIH-sponsored randomized, double-blind, placebo-controlled trial of anticoagulation in patients with certain types of pulmonary arterial hypertension.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

Voting

62 net votes
68 up votes
6 down votes
Active

Goal 2: Reduce Human Disease

Fibrosis Across Organs: Bringing Together Investigators of Fibrosis of the Heart, Lungs and Bone Marrow

Fibrosis can affect essentially any tissue or organ, including the heart, lungs and bone marrow. Effective anti-fibrotic therapy has long been elusive, and transplantation has been the only therapy capable of restoring patient function as fibrotic diseases progress to organ failure. Although these diseases present clinically with organ-specific manifestations, they are now thought to share many common pathogenetic mechanisms. ...more »

Submitted by (@amtager)

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

Details on the impact of addressing this CQ or CC :

In the aggregate, diseases characterized by fibrosis have been estimated to account for up to 45% of developed world deaths. Fibrotic diseases addressed by the NHLBI include heart failure with preserved ejection fraction (HFpEF), idiopathic pulmonary fibrosis (IPF), and myelofibrosis (MF), among many others. Each fibrotic disease represents an area of great unmet clinical need, as patients suffer and die with no or limited effective disease-modifying therapies. The impact of developing effective therapies for each of these diseases individually would be great; the impact of developing therapies effective for the entire class of fibrotic diseases across organs would truly be enormous. The clinical burden of HFpEF is staggering – more than 650,000 new patients are diagnosed with heart failure in the US each year, half with diastolic dysfunction. Although not as prevalent, IPF and MF are particularly lethal. IPF has a median survival of approximately three years. MF is arguably the most aggressive of the myeloproliferative disorders and is associated with significantly shortened survival. Although agents such as spironolactone have been unable to treat fibrosis in HFpEF as yet, two anti-fibrotic drugs, pirfenidone and nintedanib, have now been shown to slow progression of IPF, and the oral JAK1/2 inhibitor ruxolitinib has been shown to improve MF survival. These early successes underscore the great impact that developing effective anti-fibrotic therapies will have.

Feasibility and challenges of addressing this CQ or CC :

This challenge could be addressed by funding research efforts to identify and therapeutically target fundamental pathogenetic mechanisms shared by fibrotic diseases across organs. Although fibrotic diseases present clinically with organ-specific manifestations, there has been a growing appreciation of that these diseases share many aspects of their pathogenesis. Fibrosis In many of these diseases results from recurrent or non-resolving epithelial or endothelial injury, followed by over-exuberant or aberrant mesenchymal cell responses. Across all organs, these processes result in the pathologic accumulation of fibroblasts and extracellular matrix, with distortion of organ architecture and loss of organ function. Core pathways leading to epithelial and endothelial cell injury and senescence, to fibroblast accumulation and persistence, and to altered matrix biochemical and biomechanical properties, are now being identified. Therapeutics developed to target these core pathways could have broad clinical applicability. Funding initiatives aimed at better the characterization of core fibrotic pathways already identified, the identification of new core fibrotic pathways, and the development of therapies to target core fibrotic pathways, could allow the NHLBI to simultaneously and cost-effectively address the great unmet needs of the large patients with any of the many devastating fibrotic diseases that affect the heart, lungs and bone marrow.

Name of idea submitter and other team members who worked on this idea : Andrew M. Tager

Voting

16 net votes
20 up votes
4 down votes
Active