Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease - Contribution of Airways Disease

What is the contribution of airways disease to acute and chronic pulmonary distress?

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 :

What is known about this topic:

 

1) Pulmonary function testing is abnormal in 80-90% of kids and 90% of adults with SCD.

 

2) SCD kids with asthma have a higher frequency of ACS and those with a history of ACS have a higher prevalence of asthma.

 

3) An elevated TRV in SCD kids and adolescents may not predict mortality but does predict reduced exercise capacity at 22 months which may be irrespective of pulmonary hypertension

 

4) Dyspnea is extremely common in adults with SCD; 50% of HbSS and 40% of HbSC adults report at least mild dyspnea on exertion. The mechanisms responsible for this are unknown.

 

5) Bronchodilators are often used to treat patients with ACS, yet their benefit is unclear.

 

6) Systemic steroids will increase the rate of rebound pain if used during a vasoocclusive crisis.

 

7) Asthma in SCD is frequently under-treated because of fears associated with systemic and even inhaled corticosteroid use.

Feasibility and challenges of addressing this CQ or CC :

Areas of Controversy:

1) Is there an inter-relationship between airway and vascular disease in SCD?

 

2) Are systemic corticosteroids safe in SCD? Are they indicated in treatment of ACS? Are they indicated for treatment of asthma exacerbations?

 

3) Are inhaled corticosteroids useful in treating or preventing ACS?

 

4) What are the mechanisms responsible for the decline in exercise capacity observed as SCD patients go from late adolescence to early adulthood?

 

5) Will more aggressive treatment of asthma prevent this decline?

 

6) What role does nocturnal hypoxemia and OSA play in disease modulation of SCD?

 

7) What are the mechanisms of the restrictive physiology observed by PFTs primarily in adults?

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 2: Reduce Human Disease

Venous thromboembolic disease (VTE) and Sickle Cell Disease

What role does venous thromboembolic disease (VTE) play as a disease modulator in Sickle Cell Disease?

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 :

What is known about this topic:

 

1) SCD is a hypercoagulable state; patients are at increased risk for VTE compared with African American controls.

 

2) Abnormalities in the coagulation system exist in SCD patients

 

3) Increased platelet activation occurs in SCD patients with an elevated TRV, but it is not clear if patients with an elevated TRV or PH have an increased incidence of VTE.

 

4) Increased risk of ischemic strokes in this population supports the notion that thrombosis is a disease modulator

 

5) Autopsy specimens of the lungs from SCD patients reveal a thrombotic arteriopathy.

 

6) Acute pulmonary embolism can be a trigger of the acute chest syndrome (ACS).

 

7) In addition to ischemic risks, SCD patients are at increased risk for hemorrhage particularly of the cerebral and retinal vasculature.

Feasibility and challenges of addressing this CQ or CC :

Areas of controversy:

1) What is the diagnostic modality of choice for acute and chronic VTE in the SCD population? V/Q scans are notoriously abnormal and often difficult to interpret, and there is a historic (but not clinically substantiated) fear of CT/A grams in these patients due to a fear that IV contrast will promote sickling.

 

2) Does VTE occur in ACS or are these all bone marrow/fat emboli?

 

3) What role do platelets play in the endothelial dysfunction of SCD?

 

4) What is the appropriate length of time for anti-coagulation after a first VTE?

 

5) What are indications for lifelong anti-coagulation in SCD patients?

 

6) What is the role of VTE in SCD patients with PH? Do these patients have an increased prevalence of VTE and are there outcome benefits for anti-coagulation in those with and without a history of VTE?

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 3: Advance Translational Research

Should Allogeneic stem cell transplantation be considered as an upfront treatment in high risk double hit DLBCL?

Double-hit lymphomas (DHL’s) are high-grade B-cell lymphomas characterized by chromosomal rearrangements of MYC gene with BCL2 and less commonly, BCL6.Large analysis of patients with de novo DLBCL have shown that conventional chemotherapy does not improve the survival of DHL Aggressive upfront chemotherapy followed by autologous stem cell transplantation (ASCT) has become a standard treatment in eligible patients. Retrospective ...more »

Submitted by (@shahram.mori.md)

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

Details on the impact of addressing this CQ or CC :

There are currently no recommendations regarding upfront allogeneic stem cell transplantation of high-risk DHL patients in CR. Harnessing graft versus lymphoma activity may be a potential strategy to improve responses in such patients

Feasibility and challenges of addressing this CQ or CC :

The challenge of this question is the definition of DHL. FISH is commonly used to characterize DHL’s but may miss a significant portion of patients with aggressive disease. Including the cohort DLBCL patients identified by IHC expands the number of patients. Majority of patients with DHL are older but the ability to perform reduced-intensity and haploidentical -transplants will increase the number of eligible patients. The use of post-transplant therapies is needed to keep the lymphoma in check while graft versus lymphoma responses take effect.

Name of idea submitter and other team members who worked on this idea : Shahram Mori

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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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Goal 2: Reduce Human Disease

Stem Cell Biology

There is a need to develop an artificial and functional hematopoietic stem cell (HSC) niche that allows for the expansion of repopulating HSCs.

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

Details on the impact of addressing this CQ or CC :

Methods to expand hematopoietic stem cells have continued to be examined extensively because stem cell numbers in the graft are important for clinical outcomes following transplantation. These numbers are particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution. Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications beyond UCB transplantation. Furthermore, these strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with hematologic disorders. Since efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, efficient expansion will require an appropriate context that is provided by the hematopoietic stem cell niche. Future studies must also evaluate how niche signals regulate stem cell function to optimize cell expansion, and proper humanized mouse models must be developed to help predict stem cell function and regulation by the niche.

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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Goal 2: Reduce Human Disease

Evidence-based holistic care for sickle cell disease

What are the best, evidence-based models to facilitate holistic care across the lifespan for individuals living with sickle cell?

Submitted by (@sicklecellwarrior)

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

Details on the impact of addressing this CQ or CC :

Unless an individual is a candidate for transplantation, sickle cell will be a lifelong challenge. Much effort has been focused in the pediatric area and on physical aspects of the disease. However, adult care and mental/psycho-social health have not been adequately addressed. A holistic approach across the lifespan would fill these gaps and perhaps lead to better health outcomes and addresses NHLBI's goal of reducing the burden of human disease.

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc. community members

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Goal 2: Reduce Human Disease

Impact of each VOC Crisis in patients with sickle cell disease

While the long term cumulative effects of frequency, duration and severity of VOC on mortality is known in SCD, there is little known about the impact of each individual crisis or the amount of damage during crisis versus background smoldering ischemia from the disease. Any effort in quantifying this for SCD in the absence of interventional agents initially, and then as a potential measurement of the benefit of drug ...more »

Submitted by (@tosinola)

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 may help science inform additional treatment options for sickle cell disease, and serve as a cornerstone for further research particularly in the realms of drug development that addresses individual components of a sickle cell crisis.

Feasibility and challenges of addressing this CQ or CC :

This is feasible but has not been chosen as a research prerogative. A challenge is that there is no current way to measure what happens internally during a VOC.

Name of idea submitter and other team members who worked on this idea : Tosin Ola, Greg Gorgas

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Goal 3: Advance Translational Research

Current State of Regenerative Medicine: Moving Stem Cell Research from Animals into Humans for Clinical Trials

Realizing the developmental and therapeutic potential of pluripotent human embryonic stem cell (hESC) derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation.

Submitted by (@xuejunparsons)

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

Details on the impact of addressing this CQ or CC :

Realizing the developmental and therapeutic potential of pluripotent human embryonic stem cell (hESC) derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient, incomplete, and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. In addition, undefined foreign or animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for derivation and maintenance of clinical-grade pluripotent hESC and lineage-specific differentiation of pluripotent hESC by small molecule induction. Such milestone advances and medical innovations in hESC research enable direct conversion of pluripotent hESC into a large supply of homogeneous populations of clinical-grade hESC neuronal and heart cell therapy products for developing safe and effective stem cell therapies. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and heart repair in the clinical setting.

Name of idea submitter and other team members who worked on this idea : Xuejun Parsons

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Goal 2: Reduce Human Disease

Family centered interventions in sickle cell

Sickle cell is a genetic disease with lifelong health consequences for affected individuals and their families. Interventions for individuals with sickle cell must be patient and family-centered.

Submitted by (@coretta.jenerette)

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 : International Association of Sickle Cell Nurses and Physician Assistants, Inc.

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Goal 3: Advance Translational Research

Deriving Cardiac Elements from Pluripotent Human embryonic Stem Cells for Heart Reconstitution

to date, the existing markets lack a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential, which has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged human heart in cardiovascular disease.

Submitted by (@xuejunparsons)

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

Details on the impact of addressing this CQ or CC :

Given the limited capacity of the heart for self-repair or renewal, cell-based therapy represents a promising therapeutic approach closest to provide a cure to restore normal heart tissue and function for CVD. There is no evidence that adult stem/precursor/progenitor cells derived from mature tissues, such as bone marrow, cord blood, umbilical cord, mesenchymal stem cells, patients’ heart tissue, placenta, or fat tissue, are able to give rise to the contractile heart muscle cells following transplantation into the heart. Despite numerous reports about cell populations expressing stem/precursor/progenitor cell markers identified in the adult hearts, the minuscule quantities and growing evidences indicating that they are not genuine heart cells and that they give rise predominantly to non-functional smooth muscle cells rather than functional contractile cardiomyocytes have caused skepticism if they can potentially be harnessed for cardiac repair. In recent years, reprogrammed or trans-differentiated adult cells, as a result of being backed by excess sum of government and private funding, have been rekindled as the adult alternates. However, major drawbacks such as abnormal gene expression, accelerated aging, immune rejection, not graftable, and extremely low efficiencies, have severely impaired the utility of reprogrammed or trans-differentiated somatic cells as viable therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Derivation of pluripotent human embryonic stem cells (hESCs) from the IVF leftover embryos has brought a new era of cellular medicine for the heart. The intrinsic ability of a hESC for both unlimited self-renewal and differentiation into clinically-relevant lineages makes it a practically inexhaustible source of replacement cells for human tissue and function restoration. Therefore, it has been regarded as an ideal source to provide a large supply of functional human cells to heal the damaged or lost tissues that have naturally limited capacity for renewal, such as the human heart and the human brain. Although a vast sum of NHLBI funding has been spent on looking for adult alternates, such as reprogramming and trans-differentiation of fibroblasts or mature tissues, so far, only human cardiac stem/precursor/progenitor cells derived from embryo-originated hESCs have shown such cellular pharmacologic utility and capacity adequate for myocardium regeneration in pharmaceutical development of stem cell therapy for the damaged human heart.

Name of idea submitter and other team members who worked on this idea : Xuejun Parsons

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Goal 2: Reduce Human Disease

Alternative treatments in sickle cell disease

There is a growing desire for the development of alternative treatments and natural therapies for the treatment of sickle cell disease.

Submitted by (@sicklecellwarrior)

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

Details on the impact of addressing this CQ or CC :

Studies have indicated higher levels of fetal hemoglobin, even moderate levels, as being capable of reducing pain episodes. Development of therapies other than hydroxyurea, may be beneficial to individuals with SCD, specifically natural compounds as opposed to chemical based drugs. Additionally, it may be beneficial to the SCD survivors and the medical community to come up with biomedical alternatives to opiates and heavy narcotics used to induce relief and quiet the discomfort of the patient, even at the risk of addiction, resulting from prolonged usage (a life time).

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc. community members

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Goal 2: Reduce Human Disease

Apheresis Medicine in the Management of Sickle Cell Disease

Despite advances in care, patients with sickle cell disease have significant morbidity and mortality. One challenge is the optimal use of simple vs exchange transfusion vs no transfusion when managing these patients. Simple transfusions lead to iron overload while exchange transfusions may expose patients to increase numbers of red blood cell units. The mechanism of benefit from transfusion (oxygen delivery vs marrow ...more »

Submitted by (@bsachais)

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

Details on the impact of addressing this CQ or CC :

SCD is the most common genetic disease in the United States affecting 100,000 individuals or 1 in 400 African American births. Pain, stroke, acute chest syndrome and priapism are common morbidities affecting patients with sickle cell disease, which often result in emergency room visits and/or hospitalizations. Despite advances in treatment, sickle cell disease is associated with significant mortality and shortened life expectancy. Defining the optimal role of red blood cell exchange and plasma exchange (which may be used to remove plasma molecules such as inflammatory factors and free hemoglobin) in the management and prevention of the complications of sickle cell disease and may not only prolong the life of these patients but is expected to improve the quality of their lives. In addition, clearly defining the indications for simple verses exchange transfusion therapy has the potential to minimize both alloimmunization to red blood cells (reported to occur in up to 75% of patients with sickle cell disease) and iron overload associated with transfusion.

 

Transfusion therapy may be efficacious to sickle cell patients by providing increased oxygen delivery to tissues and/or decreasing the amount of sickle hemoglobin present by suppression of erythropoiesis. Understanding the relative contributions of these mechanisms will assist with optimal use of transfusion therapy as well as inform the development of novel alternative therapies

Feasibility and challenges of addressing this CQ or CC :

Multi-center trials should be feasible, given the number of patients with sickle cell disease in the US. Participation by larger academic centers which care for sickle cell patients should facilitate trials. Methods for automated red cell exchange and plasma exchange are available and in common use at many centers. Great interest exists among physicians caring for sickle cell patients (as exemplified by the recent NIH consensus document and ASFA sickle cell consensus conference) which is a strength of this proposal. Challenges include agreement on standard treatment protocols across centers and long term follow up of patients. Maintaining vascular access in sickle cell patients is another challenge when performing apheresis procedures on sickle cell patients

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

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