Showing 7 ideas for tag "biological"

Goal 3: Advance Translational Research

Arrhythmia Therapies Based on Understanding Mechanisms

There is a need to translate these new insights of genetic, molecular, cellular, and tissue arrhythmia mechanisms into the development of novel, safe, and new therapeutic interventions for the treatment and prevention of cardiac arrhythmias.

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

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Reduced socioeconomic burden of cardiac arrhythmias. Development of new technologies and recognition of new arrhythmia mechanisms.

Feasibility and challenges of addressing this CQ or CC

Several studies have already recognized the unexpected antiarrhythmic effects of some therapies intended for other cardiovascular disease. For example statins, aldosterone blockers, and possibly some essential fatty acids may reduce arrhythmia burden in patients receiving these interventions. Clinical trials should be developed to demonstrate the efficacy of these interventions, and arrhythmia endpoints, including those for atrial fibrillation and sudden cardiac death, should be incorporated into other large clinical trials. Research into novel antiarrhythmic might focus on (a) drug development; (b) cell/gene-based therapy and tissue engineering; and (c) improvements in development and use of devices and ablation to prevent or inhibit arrhythmic electrical activity. Continued research might also focus on targeting of upstream regulatory cascades of ion channel expression and function. Continued antiarrhythmic strategies might include the exploration of novel delivery systems (e.g., utilizing advances in nanotechnology and microelectronics), biological pacemakers, AV node repair/bypass, and treatment and/or reversal of disease-induced myocardial remodeling and tachyarrhythmias. Evaluation of new therapies should include a cost analysis. Studies in both children and adults with congenital heart are needed. New interventions might include new pharmacologic approaches as well as advances in electrophysiologic imaging and improved approaches to ablation.

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

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Goal 3: Advance Translational Research

Development of Novel Apheresis Adsorption Technologies to More Effectively and Safely Treat Hematologic Diseases

Current FDA approved apheresis technology currently uses elutriation/centrifugation separation techniques to remove pathologic cellular and/or plasma elements. These techniques are non-specific, limited by inefficient removal kinetics and often require considerable blood product exposure. Despite tremendous improvement in our understanding of the pathophysiology of a variety of disease, our ability to treat many of... more »

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

Details on the impact of addressing this CQ or CC

More efficient and novel means of selectively removing pathologic cellular and/or plasma elements are needed when a disease specific pathologic cellular element or plasma element is identified (i.e. anti-RBC autoantibodies in patient with severe autoimmune hemolytic anemia, anti-platelet antibody in patients with autoimmune thrombocytopenic purpura, anti-platelet factor four antibodies associated with heparin associated thrombocytopenia, complement fixing, donor specific antibodies in antibody mediated cardiac rejection, antibodies implicated in catastrophic antiphospholipid syndrome, mediators of the inflammatory response in sepsis, etc. ).

These are especially needed in patients who are critically ill and in need of rapid removal of these pathologic blood elements. Selectively and rapidly removing disease associated cellular and/or plasma elements while returning the remainder of the patient’s cells and/or plasma can minimize additional blood product exposure with its attendant risks, reduce duration of treatment significantly, and offer new forms of treatment either not available in the U.S. or not previously considered.

Feasibility and challenges of addressing this CQ or CC

Selective removal of pathologic plasma elements has been demonstrated by the development of selective adsorption columns which bind inflammatory mediators and immunoglobulins, but are not currently being used in the U.S. Current technology exists to remove specific pathologic plasma elements. For example, immunoadsorption technology, which incorporates polyclonal sheep anti-human IgG antibodies bound covalently to sepharose columns can remove >98% of all IgG subclasses after multiple treatment sessions. Similar effect can be obtained by Protein A sepharose column (Prosorba) technology which had been approved for use by the FDA for rheumatoid arthritis; however, in 2006 the manufacturer stopped producing the column due to financial reasons. Clearly, research into the use of these columns in the context of well designed, randomized clinical trials would be readily feasible with the appropriate IND and require industry support.

Furthermore, the technology that is used to couple sheep anti-human IgG antibodies to sepharose, can used to create antigen specific adsorption columns for removal of specific pathologic antibodies, for example, anti-PF4 antibodies that are involved in heparin associated thrombocytopenia, or Clq dependent (C1q) donor specific HLA antibodies that are involved in antibody mediated cardiac rejection. Industry support/small business grant support will be needed for development of these columns in addition to clinical trials demonstrating efficacy

Name of idea submitter and other team members who worked on this idea Edward Wong on behalf of ASFA

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112 up votes
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Goal 3: Advance Translational Research

Novel Cell Apheresis Technologies to Treat Hematologic Diseases

Current FDA approved apheresis technology uses elutriation/centrifugation or filtration separation techniques to remove pathologic cellular and/or plasma elements. Currently these techniques are non-specific, limited by inefficient removal kinetics and often require considerable blood product exposure. Despite tremendous improvement in our understanding of the pathophysiology of a variety of disease, our ability to... more »

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

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Novel means of selectively removing unique cellular elements involved in disease modulation are needed. For example, microparticles (MPs) have been implicated in a variety of biological processes such as: a) coagulation (e.g. platelet MPs has shown to be 50-100 times more procoagulant than activated platelets), b) oxidative stress (e.g. promotion of oxidative stress via endothelial-, monocyte-, or lymphocyte-derived MPs), and c) inflammation (e.g. acute lung injury in a rat model of acute lung injury). In regards to specific hematologic disease, the hypercoagulability associated with sickle cell disease, for example, may be the result of chronic hemolysis and circulating cell-derived MPs originating from activated platelets and erythrocytes. Endothelial progenitor cells when infused into patients with acute myocardial infarction have been shown to improve ventricular ejection fraction, cardiac geometry, coronary blood flow reserve and myocardial viability. Finally, apheresis for cells of the immune system such as T regulatory cells, cytotoxic T cells, monocytes, dendritic cells, and NK cells will be useful in immunotherapy approaches to hematologic disease. Removal of unique cellular elements may result in amelioration/treatment of associated diseases, or conversely, infusion of these cellular elements may be used to treat disease via a cellular therapy approach. Currently, apheresis methodologies that can selectively remove these unique cellular elements do not exist

Feasibility and challenges of addressing this CQ or CC

Large scale cell separation of unique cellular elements requires new approaches. Although there are no prototypic cell separation devices that can be used for clinical purposes, the emergence of microfluidic technologies have demonstrated alternatives to current cell separator technology. For example, microfluidic technology has utilized imaging/optical signal-based, magnetic, dielectrophoretic, mechanical/hydrodynamic, and molecular cell surface recognition principles to effect cell separation. Recently, acoustic separation of tumor from normal cells has been developed and offers a unique method for label free cell separation. Clearly, research into the use of these cell separation technologies on a clinical scale would require significant research and development/small business grant support and industry input with eventual need for clinical trials of these new devices to demonstrate utility.

Name of idea submitter and other team members who worked on this idea Edward Wong on behalf of ASFA

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139 up votes
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Goal 3: Advance Translational Research

Develop an Effective and Functional Biological Pacemaker

There is a need to develop a biological pacemaker for pediatric patients that would react to neurohumoral factors that normally modulate heart function, as well as adapt to the growing heart.

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

Details on the impact of addressing this CQ or CC

Reduce risks associated with the increasing use implantable pacemakers. Increase reliability of artificial electrical pacemakers.

Feasibility and challenges of addressing this CQ or CC

Animal studies have already demonstrated feasibility of cell- and gene-based as well as hybrid approaches.
The introduction of implantable medical devices using electrical impulses through electrodes placed in the heart to regulate its beating in patients whose native cardiac pacemakers fail— i.e., implantable electronic pacemakers— have permitted hundreds of thousands of individuals to live extended, relatively normal lives. Many advances since the introduction of implantable pacemakers into medical practice during the latter half of the 20th century have improved reliability, but their use still carries significant risks; e.g., lead fracture, infection, malfunction, and the need for replacement.
To date experimental cell therapy, gene therapy, and hybrid approaches have been used to create biological pacemakers in animal models. These incorporate the use of human embryonic stem cells or induced pluripotent stem cells or overexpression of the transcription factor, TBX18, to produce functional biological pacemakers in large animal models. Other gene therapy approaches have also been used to generate functional biological pacemakers in animals. These include overexpression of ion channels impacting diastolic membrane depolarization and excitability in non-pace making regions of large animal hearts. Beta-2 receptor or adenylyl cyclase overexpression represent other strategies that have been employed. Finally, a hybrid approach has used human mesenchymal stem cells loaded with the pacemaker gene HCN2is to induce pacemaker activity in large animals. Thus multiple approaches exist and collaboration is needed between investigative groups to overcome the challenge of creating and testing an effective and reliable biological pacemaker in humans.

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

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Goal 2: Reduce Human Disease

International collaboration for genetic and metabolic research on specific human population

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

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

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

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Goal 2: Reduce Human Disease

Define the biological basis, new diagnostics and therapeutics for severe sarcoidosis phenotypes

Sarcoidosis affects individuals of all races and ages and both genders, although it tends to cause significant morbidity and mortality for people in the prime of their productive life. Women, minorities and underserved populations tend to be more affected. Recent studies suggest that sarcoidosis and its severe manifestations, such as cardiac, neurologic and end stage pulmonary disease' are increasing, While the current... more »

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

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Increasing our understanding of the biological basis of sarcoidosis, its more severe phenotypes, and resolution of disease, will help improve detection and personalized management and treatment of this disease, ultimately reducing disease burden. With the current availability of epidemiologic, genetic, genomic and epigenetic tools and studies, as well as buy in from sarcoidosis patient groups, we are poised to address why some people develop more severe forms of this disease. While genetic variants are associated with sarcoidosis, the specific variants responsible for disease risk and that dictate disease activity are largely unknown. The results of studies to date suggest that other susceptibility factors or forms of genetic regulation must act in concert with exposure in the development of sarcoidosis. Growing data in other immune-mediated diseases suggests that epigenetic mechanisms in combination with genetic susceptibility and environment may help explain disease risk. By understanding these genetic, genomic and epigenetic factors, and better defining the natural history of sarcoidosis, interventions can be tested and undertaken to potentially prevent or treat the development and or progression of this devastating disease.

Feasibility and challenges of addressing this CQ or CC

The care and management of individuals with sarcoidosis is not well standardized. This has been hampered by a lack of understanding of the natural history, which appears to vary significantly. As a result, undertaking studies to define the pathobiology of this disease is biased based on the centers and researchers involved. There have been few limited multi-center studies of sarcoidosis, except for pharmaceutical trials. In the past few years, NHLBI has funded the GRADS study, a cross-sectional multi-center study, laying the ground work for needed longitudinal multi-center studies of the biological basis of disease. With involvement from a larger sarcoidosis research community and the ability to undertake large scale studies to not only define the epidemiology of this disease, but also the pathobiology of disease based on integrative Omics, new personalized diagnostics and therapeutics can be developed and tested to help address the burden of sarcoidosis.

Name of idea submitter and other team members who worked on this idea Lisa Maier, Nabeel Hamzeh, Tasha Fingerlin, Ivana Yang, Brian O'Connor, Elliott Crouser

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Goal 2: Reduce Human Disease

10. What biological variables are most influential in the development and clinical outcomes of heart disease and what can be don

Given that approximately 64 percent of women who died suddenly of CHD had no previous symptoms4 and that traditional risk factors and scores underestimate CHD risk in women, there is a need to identify unique markers for women at risk for CHD60.

 

( from 10 Report)

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

Details on the impact of addressing this CQ or CC

Early detection and correction of such variables as elevated cholesterol, hypertension, diabetes and cigarette smoking, can reduce atherosclerosis (the main cause of CHD) and improve outcomes. These are modifiable to some extent with changes in lifestyle, improved diet, exercise and smoking cessation. Psychosocial risk factors, such as low socioeconomic status, anxiety, and depression have also been linked to CHD and should be evaluated.
There are also biomarkers, biomediators, neurohormones, and surrogate markers which can signal CHD. Some of these can be modified, including

• neurohormones which are part of the renin-angiotensin-aldosterone system that directly impact angiotensin II and arginine vasopressin1, 61, 62
• markers of the inflammatory processes such as C-reactive protein which may be a useful predictor of CVD and correlates significantly with future risk of developing hypertension63, 64
• markers of heart failure such as B-type natriuretic peptide
Surrogate markers of atherosclerosis and CHD risk include left ventricular hypertrophy, intima-media arterial wall thickness, proteinuria and microalbuminuria, endothelial dysfunction, coronary calcification and anemia1, 62.

Feasibility and challenges of addressing this CQ or CC

Research shows that a variety of treatments – from lifestyle/behavioral changes, medications, and interventional treatments – can interrupt the progression of CHD. Further research is needed to demonstrate whether lifestyle and behavioral changes in women with known or suspected CHD can improve prognosis. Innovative approaches to care management that encourage changes in lifestyle should be considered. These include customized care management and the use of multidisciplinary teams of health practitioners who coordinate care for women at risk. Further research is needed to determine whether reducing or minimizing the novel biomarkers associated with CHD will result in lower mortality rates.

Name of idea submitter and other team members who worked on this idea Susan M. Campbell, WomenHeart Scientific Advisory Council

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