Showing 6 ideas for tag "therapeutic"

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)

Details on the impact of addressing this CQ or CC

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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86 up votes
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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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93 net votes
112 up votes
19 down votes
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Goal 2: Reduce Human Disease

Lipid apheresis as adjunct therapy in peripheral vascular disease

What is the roll of inflammation and how does lipid apheresis alter inflammation in peripheral vascular disease when added to standard therapy and/or when used alone? Does lipid apheresis result in long-term improvement with reduced morbidity, mortality, and expense compared to standard therapy?

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 prevalence of peripheral vascular disease (PVD) in the United States is estimated to be 5.9%, affecting up to 20% of adults over the age of 65. Therapy for PVD is vascular surgical intervention for limb ischemia; combined with medical therapy and anti-platelet agents but morbidity and mortality remains high. Low density lipoprotein cholesterol (LDL-c) is associated with increased risk for development and progression of PVD. Preliminary studies of the use of lipid apheresis have demonstrated improvement in symptoms and a variety of laboratory measures with decreased morbidity when added to standard therapy. The mechanism of this treatment may go beyond reducing LDL-c as the columns also affect levels of inflammatory cytokines, alter blood rheology, and affect other lipids.

Feasibility and challenges of addressing this CQ or CC

Currently two lipid apheresis devices have been cleared by the Food and Drug Administration and are in use in the United States. The presence of cleared devices, the large number of affected patients, and availability of testing for lipoproteins, fibrinogen, CRP, PAI-1, IL-6, IL-17, IL-1, IL-10, INF-γ, VEGF, PGI2, IGF-I and rheology factors make the enrollment and evaluation of patients into a clinical trial examining the use of this treatment of PVD feasible. Challenges for the performance of a clinical trial would include the limited number of centers offering lipid apheresis, the chronic nature and length of time needed to perform lipid apheresis, and the expense of the lipid apheresis devices and disposables.

Name of idea submitter and other team members who worked on this idea Bruce Sachais on behalf of ASFA

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96 net votes
116 up votes
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Goal 3: Advance Translational Research

Immunologic predictors of cardiac function following apheresis for dilated cardiomyopathy

Apheresis has been used to treat dilated cardiomyopathy yet the mechanism of action and predictors of response are unknown and clinical utility needs to be confirmed. What is the clinical utility, mechanism of action, and predictors of response?

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

Details on the impact of addressing this CQ or CC

Dilated cardiomyopathy (DCM) is progressive ventricular enlargement and dysfunction, responsible for 10,000 deaths and 46,000 hospitalizations in the U.S. annually. It is the primary indication for heart transplantation. It may represent viral infection triggered autoimmunity with myocardial autoantibodies identified in 80% of patients and higher autoimmune disease prevalence in patients.

Immunoadsorption and plasma exchange have been used to treat DCM. Staphylococcal protein A agarose (SPAA) columns have the largest published evidence with improved left ventricular (LV)ejection fraction, decreased LV circumference, decreased BNP, improved exercise tolerance, improved oxygen uptake, increased regulator T-cells, decreased stimulatory T-cells, decreased costimulatory T-cells, and improved quality of life. Decreased morbidity and mortality with fewer patients progressing to transplantation and lower health care costs has been described. Given organ shortages, morbidity, and expense of transplantation, a treatment that delays or avoids transplantation would improve health and reduced costs.

Immunological variables such as IgG subtypes, Th1, Th2, Th17 and T regulatory cell number, associated cytokines, and nuclear transcription factors implicated in DCM pathogenesis could correlate with LV function following apheresis and identify apheresis selection criteria and offer a novel mechanism to investigate how autoantibody reduction influences cellular immune components.

Feasibility and challenges of addressing this CQ or CC

DCM is the most common cause of cardiac transplantation with a large number of patients available for study. There are numerous standardized tools for measuring patient quality of life and function for those suffering from congestive heart failure. There are readily available assays for examining potential immunologic variables. If TPE is examined, this procedure is readily available.

Challenges would include the fact that the immunoadsorption columns that have been used are not cleared by the Food and Drug Administration and therefore there is limited to no experience with their use in the U.S. Immunologic evaluations could also require endomyocardial biopsy which represents an invasive procedure which could limit patient enrollment and increase risk.

Name of idea submitter and other team members who worked on this idea Bruce Saichais on behalf of ASFA

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54 net votes
80 up votes
26 down 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)

Details on the impact of addressing this CQ or CC

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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118 net votes
139 up votes
21 down votes
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Goal 3: Advance Translational Research

Study on the Immunologic Effects of ECP (Extracorporeal Photopheresis)

The clinical use of extracorporeal photopheresis (ECP) is expanding. It is known that dendritic cells plays critical role key to its efficacy, but exactly how ECP impacts other immune components and their interactions is not fully understood. There are many unanswered questions such as: “ What are the critical factors in ECP that result in a shift of the dendritic cell population from immune activating to immune tolerant?... more »

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

Details on the impact of addressing this CQ or CC

Further basic science research is necessary to elucidate how these cellular activities are functionally integrated and regulated.
It is critical to understand the role of ECP in immunomodulation and tumor immunotherapy, thus better clinical protocol can be developed with optimal immune balance to achieve therapeutic target and minimize side effects.

Feasibility and challenges of addressing this CQ or CC

Studying immunomodulation in ECP patients offers a true bench to bedside opportunity. Experimental protocols can utilize in vitro, animal and clinical study designs targeted at immunotolerance and tumor vaccines
There are a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. Funding support is critically needed in this area.

Name of idea submitter and other team members who worked on this idea Yanyun Wu on behalf of ASFA

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91 net votes
108 up votes
17 down votes
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