Goal 3: Advance Translational Research

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

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

Submitted by (@chanduvem)

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

Details on the impact of addressing this CQ or CC :

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

Feasibility and challenges of addressing this CQ or CC :

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

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

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

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6 up votes
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Goal 2: Reduce Human Disease

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

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

Submitted by (@skrenrich)

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

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

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2 net votes
6 up votes
4 down votes
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Goal 3: Advance Translational Research

Direct Upregulation of Antioxidant Defenses as a Therapeutic Strategy

Clinical trials involving administration of antioxidants such as vitamin C or vitamin E as therapeutic strategies for cardiovascular diseases associated with oxidant stress have proven to be surprisingly disappointing. A particularly attractive alternative approach is direct upregulation of endogenous antioxidant defenses such as NRF2 via dietary approaches. NRF2 is a master antioxidant and cell protective transcription ...more »

Submitted by (@jlombard)

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

Details on the impact of addressing this CQ or CC :

Direct upregulation of endogenous antioxidant defenses such as NRF2 via dietary approaches will avoid the well known caveats of drug-based approaches such as off target effects and detrimental side effects. Dietary supplements such as Protandim are already available; and beneficial effects of other NRF2 up-regulators such as resveratrol and sulforaphane are beginning to be recognized. The dietary approach is minimally invasive and has high preventative value.

Feasibility and challenges of addressing this CQ or CC :

Addressing this CQ is clearly feasible, as dietary supplements are currently available for humans, and the beneficial effects of foods containing compounds that upregulate the NRF2 system, e.g., broccoli, cauliflower, red wine, and grape juice are currently recognized. One challenge in addressing this question in animal models to date is that the only genetic model lacking NRF2 is a knockout mouse model, which have substantial limitations for in vivo physiological studies due to their small size. However, a recent R21 grant (#1R21OD018309-J. H. Lombard, P.I.) has allowed the development of a NRF2 knockout rat model which is better suited for physiological studies than the mouse model. In addition, the techniques used to develop the NRF2 knockout rat can be applied to multiple disease-sensitized strains, e.g., the Dahl salt-sensitive rat. Fawn Hooded Hypertensive rat, Obese Zucker rat, etc. Similar disease sensitized rodent genetic strains are not available in mice.

Name of idea submitter and other team members who worked on this idea : Julian H. Lombard

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Goal 2: Reduce Human Disease

Gene Therapy for Rare Lung Diseases

Accelerating the research to find suitable viral vectors and delivery systems to inhale gene therapy deeply into the lungs. Distal therapy is important for several fatal lung diseases. This is urgent and critical research.

Submitted by (@dappell)

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

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3 net votes
5 up votes
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Goal 2: Reduce Human Disease

The Use of Therapeutic Apheresis to Reduce Circulating Levels of Galectin-3 and other Cancer and Inflammation Promoting Factors

Inflammation plays roles in cancer initiation, promotion, and progression. Elevated circulating galectin-3 (Gal-3) protein and other cancer and inflammation promoting factors (CIPFs) such as C-reactive protein and VEGF are associated with tumorigenesis and may play causative roles. Plasma Gal-3 is a biomarker, prognosticator, and pathogenic mediator of diverse cancers and is emerging as a therapeutic target. Preliminary ...more »

Submitted by (@elaine)

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

Details on the impact of addressing this CQ or CC :

Apheresis therapy in a clinical setting, both alone and in combination with conventional protocols, shows great potential to enhance treatment regimens, reduce dosage and side effects, improve drug deliver to target tissues, reduce long term treatment related morbidity and improve outcomes with significant benefits for patients with a broad range of cancer types and stages.

Feasibility and challenges of addressing this CQ or CC :

The need for well designed, randomized clinical trials would be readily feasible with the appropriate IND. Grant support will be needed for further development of this concept, as well as to develop columns with more optimized and specific capabilities, in addition to clinical trials demonstrating efficacy.

 

Apheresis is highly underutilized and underfunded in the US, while Apheresis research and development is much more advanced and widely utilized in Europe and Asia.

Name of idea submitter and other team members who worked on this idea : Isaac Eliaz, MD

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40 up votes
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Goal 1: Promote Human Health

Role of non-coding RNAs in cardiovascular biology and disease

Noncoding RNAs field is still in its infancy. It includes microRNA and long-non-coding RNA. Recent studies show that Non-coding RNA play important roles in the regulation of tissue homeostasis and pathophysiological conditions. miRNA-based therapeutics showed promising results in numerous animal models of heart failure, cardiac hypertrophy, fibrosis and hyperlipidaemias, and showed success in in-human clinical trial ...more »

Submitted by (@totaryjainh)

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

Details on the impact of addressing this CQ or CC :

Genetic studies using gain- or loss-of- function approaches suggest that lncRNAs can indeed contribute to cardiac or vascular dysfunction. Moreover, targeting of lncRNAs in a cell-selective manner might be possible to treat cardiovascular disease. This may open up the opportunity for the development of new therapeutic strategies.

Feasibility and challenges of addressing this CQ or CC :

The regulation of lncRNAs has been documented in different disease models however the function is only known for a few lncRNAs. The fact that most lncRNAs are poorly conserved and are expressed as various transcript variants challenges the identification of specific biological functions and mechanisms of action. Combination of microRNA target sequesnces and long-non-coding RNA may allow for a novel cell-selective therapies.

Name of idea submitter and other team members who worked on this idea : Hana Totary-Jain

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10 up votes
5 down votes
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Goal 1: Promote Human Health

Combinatorial intervention of immune dynamics to combat cariovascular disease

Human health and disease are modulated by complex and inter-connected dynamic processes. With particular significance, a well-balanced immune environment may play a key role in maintaining health and preventing the pathogenesis of cardiovascular disease. Defining the dynamic programming and balance of immune environment will be the key for combinatorial therapies to reset homeostasis.

Submitted by (@lwli00)

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 : Liwu Li

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8 net votes
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2 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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149 up votes
34 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 2: Reduce Human Disease

How can we more safely deliver stem cells to Sickle Cell patients

Newer therapies using gene correction, rather than gene addition, are needed for sickle cell disease. Even with this potential advantage, there needs to be a way to safely deliver gene corrected HSC to the sickle cell patient. Chemotherapy is poorly tolerated, and often is the reason patients do not choose the BMT option. What is the status of other less toxic non myeloablative approaches, and how can they best be ...more »

Submitted by (@freddigoldman)

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

Details on the impact of addressing this CQ or CC :

would open up opportunities for more patients to get cured of their sickle cell disease without co morbidity of the BMT process

Feasibility and challenges of addressing this CQ or CC :

Need to develop animal models and also newer marrow niche clearing agents.

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67 up votes
16 down votes
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Goal 2: Reduce Human Disease

Immunologic Treatment of Hematologic Malignancies

How can the effectiveness of existing curative therapies be improved for allogeneic hematopoietic stem cell transplantation?

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

Details on the impact of addressing this CQ or CC :

Much remains to be understood about immunotherapies in order to facilitate their broad use in the treatment of hematologic disorders. While studies to date have demonstrated significant potential applications, longer-term studies are necessary to further improve the profile of these therapies, including enhancing their overall efficacy while reducing associated toxicities. The efficacy of existing curative therapies can be enhanced by evaluating the mechanisms involved in producing cytokine release syndrome; a condition which has been observed in several patients receiving this therapy. Furthermore, a careful grading scheme to predict toxicity so as to guide the development of preventive and therapeutic strategies is also required. Target identification is another important issue to advance the field. While targeting CD19 appears to be promising, it results in loss of B-cell immunity and requires prolonged immunoglobulin replacement therapies and/or allo-transplantation and new immunologic targets need to be identified in both B cell and T cell malignancies as was as acute and chronic myeloid leukemias. Minimizing the off-tumor target-mediated toxicity of both CAR T-cell and checkpoint blockade therapies would help optimize their utility.

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

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63 up votes
20 down votes
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