Goal 3: Advance Translational Research

To facilitate innovation and accelerate research translation, knowledge dissemination, and implementation science that enhances public health.

Goal 3: Advance Translational Research

A Pipeline for Investigator- Initiated Translational Science

How might the NHLBI effectively encourage and support its investigators to collaborate with strategic partners to pursue the early translation of their HLBS discoveries into new diagnostics and therapeutics? The critical challenges to effective early translation of discovery science experienced by the investigator community include: 1. The need for translational skills development, training and guidance 2. Need for ...more »

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 :

During the past several decades there have been revolutionary changes in technology that have enabled an unprecedented understanding of basic biologic and pathobiologic phenomena. However, there has not been a concomitant increase in novel technologies to prevent, diagnose, and treat disease. While NHLBI funds thousands of R01 grants that support mechanistic research, only a small percentage moves the basic discoveries into the pre-clinical space, a critical step in fulfilling NHLBI’s mission. An analysis of the Division of Blood Diseases applications for the FY 2012, showed that while 32% (174/541) of the unsolicited applications (RO1, R21, PO1) had at least one early translational component, only 15% went beyond proof of concept and only 3% included early phase clinical trials. Patent filings, a main gateway to translation, are another way to estimate the translation of NHLBI discovery science. A survey of 90 NHLBI investigators, randomly selected across all three Divisions, found 76% of the investigators had no patent activity over a 10 year period and 12% accounted for 82% of all the patent activity. These data suggest that there may be barriers to investigators being able to realize the translational potential of promising discoveries beyond proof of concept. NHLBI needs an overarching, coordinated, and efficient plan to encourage and support investigators in their independent pursuit of translational research.

 

The creation of an integrated, facilitative programmatic pathway at NHLBI that would leverage existing NIH resources to ease the major barriers to translation of scientific discovery in the investigator community by:

•Providing skills development training and guidance for investigators wishing to do translational research

•Coordinating the support of all pre-IND phases of translational science

Facilitating reproducible pre-clinical research in animals, including animal and humanized models, medical chemistry, pharmacological toxicology

•Providing support for early phase or adaptive design clinical trials

•Ensuring scientific review that is available and tailored to all phases of investigator-initiated translational science

•Establishing a robust system for ongoing portfolio analysis and program evaluation as well as metrics for evaluating programmatic outcomes

 

The creation of an integrated, facilitative programmatic pathway at NHLBI that would leverage existing NIH resources to ease the major barriers to translation of scientific discovery in the investigator community by:

•Providing skills development training and guidance for investigators wishing to do translational research

•Coordinating the support of all pre-IND phases of translational science

Facilitating reproducible pre-clinical research in animals, including animal and humanized models, medical chemistry, pharmacological toxicology

•Providing support for early phase or adaptive design clinical trials

•Ensuring scientific review that is available and tailored to all phases of investigator-initiated translational science

•Establishing a robust system for ongoing portfolio analysis and program evaluation as well as metrics for evaluating programmatic outcomes

Feasibility and challenges of addressing this CQ or CC :

The overwhelming response to NHLBI translational initiatives suggests a critical mass of investigators willing and able to explore the translational potential of their discoveries. The barriers to the continuous receipt of translational applications outside of the RFA mechanism have been identified and the proposed model for a competitive peer-reviewed process that spans the early translational pipeline has already been successfully implemented in at least one other NIH Institute. Adopting this model, the pipeline, as envisioned, would mostly consist of facilitative PAs and Review would not require a major up front expenditure of NHLBI targeted funding.

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

Voting

196 net votes
226 up votes
30 down votes
Active

Goal 3: Advance Translational Research

DEVELOPMENT OF BIOMARKERS FOR SLEEP INSUFFICIENCY, CIRCADIAN DISRUPTION AND SLEEP DISORDERS

There is an urgent need to develop quantifiable biomarkers for acute sleep loss, chronic sleep insufficiency, circadian disruption and sleep disorders such as obstructive sleep apnea. These problems are highly prevalent but currently we do not have biomarkers to use for case identification, prognosis, or assessing response to therapy. There are currently small studies that indicate the feasibility. A recent workshop ...more »

Submitted by (@jnoel0)

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 following will be the impact of addressing this critical challenge:

 

1. Having an assessment that can be used following a crash to assess the level of sleep loss of the driver.

2. Having a method to assess chronic sleep insufficiency as a potential pathogenetic process in patients with cardiovascular disease, hypertension, etc.

3. Having a method to estimate circadian phase so that in patients with chronic insomnia one can identify individuals with delayed sleep phase.

4. Having a technique to establish magnitude of circadian disruption to assess its role in pathogenesis of diseases such as cardiovascular disease.

5. Add a molecular biomarker to other techniques to screen for obstructive sleep apnea in high risk populations such as obese commercial drivers.

6. Utilize a biomarker signature to identify who with obstructive sleep apnea will be particularly at risk for downstream consequences such as cardiovascular disease.

7. Develop the equivalent of HbA1C to assess therapeutic response to CPAP

Feasibility and challenges of addressing this CQ or CC :

The first challenge is to identify a signature for each of these use cases. This will require initial studies in a small number of well phenotyped subjects with all the “-omic” techniques. Thereafter, these multiple cohorts, already available with blood samples, etc. and relative phenotype can be used for validation purposes.

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

Voting

179 net votes
240 up votes
61 down votes
Active

Goal 3: Advance Translational Research

Allogeneic transplantation as a safe and universally available therapeutic strategy for treating non-malignant blood diseases

Can new advances in allogeneic blood or marrow transplantation (BMT) make the procedure a safe and universally available therapeutic strategy for treating non-malignant blood and immune disorders such as sickle cell anemia, thalassemia, aplastic anemia, and severe combined immune deficiency?

Submitted by (@rjjones)

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 ability of allogeneic blood or marrow transplantation (BMT) to cure diverse non-malignant diseases is well-documented. However, widespread use in diseases such as sickle cell anemia that cause substantial morbidity and shorten life but are not immediately life-threatening, has been limited by transplant-related toxicity and mortality especially in the majority of these patients who lack HLA-matched donors. Several new therapeutic approaches now exist that are promising strategies, separately or in combination, for addressing issues of donor availability, graft rejection, organ toxicity and acute and chronic graft-versus-host disease more effectively. Evaluation and refinement of these therapeutic strategies in both preclinical and Phase I-III clinical trials now offers a real possibility that allogeneic BMT could be applied early in the course of these diseases, allowing normal growth, development, quality of life and lifespan. If successful, allogeneic BMT offers a major advantage over gene therapy approaches even if such approaches become possible in the future; i.e., allogeneic BMT can be done with low-dose, non-toxic conditioning while gene therapy requires high-dose myeloablative therapy which not only can be toxic/fatal to these patients who often have end-organ dysfunction but also universally induces infertility, a major concern of patient groups who usually survive beyond child-bearing years.

Feasibility and challenges of addressing this CQ or CC :

There are now single institution and registry (CIBMTR) data showing that related haploidentical allogeneic BMT using post-transplantation cyclophosphamide (PTCy) produces results similar to those seen with HLA-matched sibling donors. Accordingly, every patient in need of allogeneic BMT now can safely undergo the procedure, including those ethnic groups (such as African-Americans and Hispanics) who are unlikely to find a donor in unrelated registries. Combining PTCy with other approaches for preventing graft-versus-host disease (GVHD) can even eliminate GVHD and transplant-related mortality. Although recurrence of malignant diseases remains an issue, especially as GVHD is eliminated, relapse is not a concern for non-malignant diseases after successful allogeneic engraftment. Moreover, the average cost of allogeneic BMT, about $150K, is a cost-savings over the long-term management of many of these diseases. The NHLBI-funded BMT Clinical Trials Network (CTN) has developed the infrastructure to rapidly and efficiently carry out large multi-institutional BMT trials. Over the last 15 year, thousands of patients have been entered on BMT CTN trials. Of note, African-Americans and Hispanics remarkably represent 30% of the accruals on one such trial, CTN1101, studying unrelated umbilical cord and related haploidentical allogeneic BMT. However, funding for the infrastructure for continuing this work remains problematic, since BMT trials generally lack corporate funding.

Name of idea submitter and other team members who worked on this idea : Rick Jones

Voting

164 net votes
214 up votes
50 down votes
Active

Goal 3: Advance Translational Research

NEW INFRASTRUCTURE FOR CLINICAL RESEARCH IN SLEEP AND CIRCADIAN DISORDERS

Much of the current clinical research on sleep and circadian research depends on cohorts designed for other purposes. While this has been helpful, such studies have limitations. These limitations are related to availability of in-depth phenotyping data and questions as to whether individuals identified in population studies are equivalent to those who present clinically with specific disorders. These concerns could ...more »

Submitted by (@jnoel0)

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

Details on the impact of addressing this CQ or CC :

Sleep and circadian disorders are extremely common. For many of these we know little about the natural history, whether different subgroups exist and effects of current therapies. Thus, developing specific registries for common sleep and circadian disorders would provide a basis for addressing these questions.

 

For some aspects, e.g., studies of inadequate sleep, impact of snoring and circadian disruption, would be facilitated by developing a specific sleep/circadian cohort with in-depth phenotyping. This strategy has worked extremely well in other areas, e.g., cardiovascular disease. The lack of this type of cohort for sleep and circadian disorders is a barrier to progress in this area. The high prevalence of these disorders and their known public health significance argue that development of such a cohort would be a game changer and accelerate progress in this new area of medicine.

 

Such a cohort could address several compelling questions:

 

a. What is the natural history of short sleep across the lifespan?

b. What is the impact of snoring? Does it lead, as has been proposed, to vibration injury to carotid arteries with accelerated vessel wall damage?

c. Are there different subtypes of individuals with the different sleep and circadian disorders?

d. What is the natural history of shift-workers and what types of shifts lead to increased risk for cardiovascular disease?

Feasibility and challenges of addressing this CQ or CC :

Problems with sleep and circadian rhythm and the relevant disorders are common. There are multiple accredited sleep centers for clinical purposes in the United Sates. They use common phenotyping platforms that could be the basis of some aspects of addressing this critical challenge. Moreover, most CTSA programs have a sleep study component. There are patient support groups for sleep apnea, insomnia, restless legs syndrome and narcolepsy. Thus, these groups could be marshaled to help in this effort. There is already a Sleep Research Network that was founded by the field itself. It is currently based on volunteer effort and there are no resources to support it. It could be the basis for future activities in this area.

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

Voting

126 net votes
186 up votes
60 down votes
Active

Goal 3: Advance Translational Research

Can we leverage exisiting registries to perform prospective trials and advance reduce the cost of doing research?

Current costs for multicenter randomized or non randomized trials are astronomical, and a major obstacle to rapid implementation of potential lifesaving discoveries. In the field of hematopoietic cell transplantation (HCT) their is a federal mandate to have a treatment outcome registry. Funds should be made available to leverage that registry to perform prospective trials either randomized or not since HCT programs need ...more »

Submitted by (@giralts)

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 would allow for rapid exploration of novel concepts. Would reduce the time and cost of doing research in the HCT field. Would allow to explore questions related to best supportive care practices in HCT

Feasibility and challenges of addressing this CQ or CC :

Very feasible. Last year we prepared a proposal in response to an RFA demonstrating that all elements are in place.

The CIBMTR has already shown that prospective observational studies are feasible and useful

Name of idea submitter and other team members who worked on this idea : sergio giralt

Voting

123 net votes
154 up votes
31 down votes
Active

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 »

Submitted by (@ewong0)

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

Voting

118 net votes
139 up votes
21 down votes
Active

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.

Voting

115 net votes
149 up votes
34 down votes
Active

Goal 3: Advance Translational Research

ESTABLISHMENT OF APHERESIS MEDICINE CONSORTIUM TO ADVANCE DEVELOPMENT OF EVIDENCE BASED THERAPIES

The apheresis medicine encompasses treatment of numerous diseases many of which are directly related to blood, lung and heart. There is a need to establish consortia for Apheresis Medicine to facilitate networking, information exchange and research collaboration among investigators, including junior investigators. These consortia would perform basic science as well as translational research and investigate the best pathways ...more »

Submitted by (@zbigniew.m.szczepiorkowski)

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 creation of one or more Research Consortia devoted to research in Apheresis Medicine would allow for the establishment and support of a core group of investigators and institutions representing key specialty areas across the spectrum of Apheresis Medicine. An initial focus would be translational research priorities. In addition, we believe that a strong U.S. based consortium would facilitate participation of international investigators and societies, which would improve patient accrual on studies, especially those patients with rare disorders or who have rare indications for apheresis therapy. Such a group would significantly enhance the likelihood of completing high quality studies.

 

There is increasing national interest in developing new registries, bio-repositories and data-repositories. Very often such efforts do not include information regarding apheresis nor do they consider apheresis information as being important data points. A centralized, well organized and sustainable registry, either established and/or new for Apheresis Medicine, would be of great value to study the outcomes of therapeutic apheresis for different disease conditions. This need is particularly relevant for rare disorders and rare indications, for which a pilot effort is already being undertaken and sponsored by ASFA- the American Society for Apheresis.

Feasibility and challenges of addressing this CQ or CC :

Feasibility: There are hundreds of thousands apheresis procedures performed each year in the US. Many of these procedures are performed in tertiary and quaternary academic medical centers. These centers have experience in education, basic science, translational research and clinical trials. Despite the low frequency of some diseases there is a real possibility of performing clinical trials in the context of multicenter consortium. Such consortium could also assist in development of new projects related to Apheresis Medicine (both basic science and clinical) which then can proceed to clinical trials quickly as the appropriate infrastructure will be created within the consortium. This infrastructure would also serve education of the new investigators.

Challenges: Standardization of approaches between different medical centers might be initially difficult, but as it has been shown many centers follow in their clinical practice ASFA designated indications. Setting up research priorities for the consortium might be challenging as well as accrual patients to clinical trials within the consortium. Though standardization of the apheresis devices is not feasible, this could be mitigated by appropriate study designs. The number of investigators in apheresis medicine is limited but the consortium may serve as a great platform to expand its numbers through collaborative efforts of involved centers.

Name of idea submitter and other team members who worked on this idea : Zbigniew M. Szczepiorkowski, Yanyun Wu on behalf of ASFA

Voting

112 net votes
131 up votes
19 down votes
Active

Goal 3: Advance Translational Research

How can we develop more selective immunosuppression for allogeneic hematopoietic cell transplantation?

Graft versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (HCT). While the use of HCT has grown significantly safer and has demonstrated broad efficacy in the setting of a broad range of blood diseases, immunosuppressive therapy has not dramatically evolved since the introduction of calcineurin inhibitor-based approaches decades ago. The availability ...more »

Submitted by (@kkomanduri)

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

Details on the impact of addressing this CQ or CC :

GVHD remains a critical problem and major barrier to the more widespread utilization of HCT, especially for nonmalignant diseases, where tolerance of treatment-related mortality is understandably low.

 

There is a compelling need for novel immunosuppressive agents that can effectively limit alloreactivity mediated by donor T and B cells, while relatively sparing pathogen-specific T cells, including those mediating antiviral T cell responses important in the post-HCT interval.

 

In the past decade, drug development has facilitated the introduction into preclinical and clinical trials of a broad range of agents that in addition to targeting pathways of interest in target cells (e.g., aberrant signaling in cancer cells) may also effectively inhibit T and/or B cell responses. Examples include hypomethylating agents (e.g., azacitidine), HDAC inhibitors (e.g., vorinostat), MEK inhibitors (e.g., trametinib) and BTK inhibitors (e.g., ibrutinib). Each of these classes of agents has been demonstrated in preclinical and/or clinical studies to also limit alloreactive T cells, and/or augment regulatory T cell responses, leading to a net reduction of alloreactivity. Unlike traditional agents (e.g., the calcineurin inhibitors) these agents appear to be more selective, and in some cases may have dual benefit in reducing relapse.

 

The NHLBI can facilitate the identification and translation to clinical practice in the setting of HCT trials of novel immunosuppressive agents.

Feasibility and challenges of addressing this CQ or CC :

Research funding targeted to improving the pipeline of novel immunosuppressive agents could have immediate and dramatic impact in the field of HCT, especially impacting its application for nonmalignant diseases. Patients lacking optimal registry donors, especially those from underrepresented minority groups, will particularly benefit from improvements in immunosuppression, as patients receiving less than optimally matched donors are at much higher risk of GVHD.

 

The NHLBI can encourage and facilitate research that tests compounds that have already passed through the drug development process, but in many cases were not intended to function as immunosuppressive agents. Compelling preclinical studies have suggested that targeted inhibition of T and B cells, and/or epigenetic modifiers can lessen alloreactivity while preserving beneficial cellular immune responses and facilitating immune reconstitution.

 

It will be far easier to appropriate therapeutic agents already developed for another purpose than to do novel drug development from scratch. In many cases, preclinical studies have highlighted the therapeutic potential in immunosuppression for agents that have been developed to treat malignancies, but yielded suboptimal success. Research that encourages the development of these drugs as part of a combined immunosuppressive/immunomodulation approach may rescue such compounds, while yielding potential dramatic advances in clinical HCT.

Name of idea submitter and other team members who worked on this idea : Krishna Komanduri, M.D.

Voting

106 net votes
129 up votes
23 down votes
Active

Goal 3: Advance Translational Research

Better disease models

Many diseases of the heart, lung and blood systems are studied using animal models, often with genetically engineered mice. However, while mice get models, humans get diseases. Too many grants are devoted to curing models, a practice encouraged by many high profile journals who want to see “proof” in a standard model of disease. Much less time, effort and money will be wasted on developing ineffective therapies if focus ...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 :

Morphologic appearance is necessary but insufficient as a criterion for validating a model. Comparative “omics” should be strongly encouraged. It is a waste of resources to develop therapies based on the effects of yet another gene knock out in something as unphysiological as atherosclerotic lesions in an ApoE knock out mouse or asthma in a mouse with eosinophilic airspace disease that largely ignores the bronchial tree or the infusion “stem cells” on cardiac function in a mouse with an experimental myocardial infarct. These are simply prominent examples of widely used standard models with little real utility. Therapies based on such approaches are likely to fail. Better models that more realistically capture phenotypic features of real diseases could lead to more promising therapies.

Feasibility and challenges of addressing this CQ or CC :

Model development is not very sexy and stands a better chance of acquiring support outside the standard study section review mechanism where proposals are judged by investigators with a vested interest in (and academic career based on) using existing models, despite their poor track records.

Name of idea submitter and other team members who worked on this idea : Jordan S. Pober

Voting

97 net votes
126 up votes
29 down votes
Active

Goal 3: Advance Translational Research

TREATMENT OF SEPSIS-MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS) UTILIZING APHERESIS BASED STRATEGIES

Sepsis, a systemic inflammatory response to infection, is the most common cause of death in non-cardiac intensive care units. The incidence and severity of sepsis have increased over the last two decades. With advances in supportive care, sepsis carries a mortality that averages 17%, however, this figure increases to 50 - 80% in Multiple Organ Dysfunction Syndrome (MODS), defined as failure of 3 or more organ systems. ...more »

Submitted by (@zbigniew.m.szczepiorkowski)

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

Details on the impact of addressing this CQ or CC :

Despite many attempts, therapeutic trials using pharmacologic agents to interrupt specific pathways of inflammation and coagulation have been unsuccessful. The failed targeted therapies include the administration of corticosteroids, monoclonal antibodies to TNF, soluble TNF receptor, antithrombin (AT), activated protein C, and tissue factor pathway inhibitor. Because it is non-selective, plasma exchange has the potential to remove deleterious mediators and restore anti-inflammatory/anticoagulant factors consumed in sepsis/MODS. There is evidence that some of the implicated mediators of sepsis can be effectively removed by plasma exchange, eg, TNF alpha and endotoxin. In addition, the normal regulatory molecules consumed during the systemic inflammatory process, such as AT, proteins C and S, and ADAMTS-13 would be replaced, which may influence the pathophysiology of MODS/sepsis. However, the mechanism of action of plasma exchange, whether removal of inflammatory mediators of sepsis or modulation of the later consequences of MODS such as sustained endothelial activation, remains unclear at the present time. Other apheresis based strategies also have been attempted but their results also require confirmation by well-designed clinical trials to answer the question of their value in treatment of sepsis.

Development of apheresis strategies which address the pathophysiology of sepsis and identify responsive patient populations would have a great societal value

Feasibility and challenges of addressing this CQ or CC :

Feasibility: the large number of patients who develop sepsis provides for significant number of potential patients who can be enrolled. More sophisticated methods of enrollment may help as many patients are not capable of providing informed consent. Establishing an apheresis consortium and collaboration with intensive care physicians will be an important step in assuring appropriate accrual of patients. The availability of apheresis devices is likely to be high in the tertiary/quaternary care medical centers where these studies can be performed. Animal models of sepsis are being investigated and are necessary for studies evaluating pathophysiology; though some apheresis strategies can be moved to clinical studies without additional preclinical developments.

 

Challenges: Identification of the patient population which responds optimally to apheresis based strategies is critical to the development of a randomized clinical trial. One study has indicated that it would be the critically ill pediatric population; however, the critically ill adult population is the largest affected group). Given the equipoise of using apheresis based strategies in the treatment of sepsis/MODS, finding patients to randomize is unlikely to be difficult. Other potential challenges include the cost of developing randomized clinical trials using apheresis, competition with other pharmacology based strategies, center bias, and the timing for initiation of the apheresis.

Name of idea submitter and other team members who worked on this idea : Zbigniew M. Szczepiorkowski; Joseph Kiss, Ed Wong on behalf of ASFA

Voting

97 net votes
115 up votes
18 down votes
Active

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 »

Submitted by (@ewong0)

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

Voting

93 net votes
112 up votes
19 down votes
Active