Goal 2: Reduce Human Disease

Disease Severity Biomarkers for Sickle Cell Disease

Can we identify biomarkers that can predict sickle cell disease severity?

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 :

Identifying reliable biomarkers that can predict severity of sickle cell disease could help doctors and patients make better decisions about a wide range of clinical decisions, including weighing the risks vs. benefits of bone marrow transplantation, chemotherapeutic manipulation of Hb F level, and gene therapy, all of which have potentially life-threatening complications.

Feasibility and challenges of addressing this CQ or CC :

Scientific advances make it feasible to identify biomarkers of disease severity. However, identifying biomarkers with good sensitivity and specificity is likely to be a challenge.

Name of idea submitter and other team members who worked on this idea : The Sickle Cell Association of New Jersey

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Goal 2: Reduce Human Disease

Hypoxia, acute chest syndrome and sickle cell disease

What markers in sickle cell disease can predict hypoxia after acute chest syndrome or pneumonia?

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 :

Understanding that sickle cell disease has a character of depriving oxygen, is there any predicators that can tell if a child will have hypoxia after experiencing acute chest syndrome or pneumonia.

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

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32 net votes
41 up votes
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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 3: Advance Translational Research

Stem Cell Biology

There is a need to develop “designer platelets” and “designer red cells,” as well as facilitate large-scale production of these products for therapeutic and diagnostic use.

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 reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of hematologic diseases. Although this technology has enabled the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, the major scientific hurdle has been the ability to create clinically meaningful functional blood products, including transplantable HSCs from differentiating iPSCs. The production of clinically functional blood products -- i.e. red blood cells derived from autologous iPSCs --could replace allogeneic products in highly immunized patients and the generation of megakaryocytes for patient-specific platelet production from iPSCs could drive significant progress in this area. Furthermore, disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders. In addition, support for scale-up and GMP processes, which are difficult to fund via the R01 mechanism will require specific grant opportunities tailored to infrastructure and process development.

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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25 net votes
53 up votes
28 down votes
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Goal 3: Advance Translational Research

The Designation of Human Cardiac Stem Cell therapy Products for Human Trials or First-in-Human Studies

For successful pharmaceutical development of cardiac stem cell therapy, the human cardiac stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials.

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 :

For successful pharmaceutical development of cardiac stem cell therapy, the human cardiac stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials. Moving stem cell research from current studies in animals into human trials must address such practical issues for commercial and therapeutic uses: 1) such human stem cells or their cardiac derivatives must be able to be manufactured in a commercial scale; 2) such human stem cells and their cardiac derivatives must be able to retain their normality or stability for a long term; and 3) such human stem cells must be able to differentiate or generate a sufficient number of functional or contractile cardiomyocytes for repair. Those practical issues are essential for designating any human cardiac stem cells as a human cardiac stem cell therapy product for investigational new drug (IND)-filing and entry into clinical trials. So far, the therapeutic effects, if any, of human cardiac stem cells in the existing market, including those derived from patients’ heart tissues, were mediated by protective or tropic mechanism to rescue dying host cardiomyocytes, but not related to myocardium regeneration.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent breakthrough stem cell technologies have demonstrated the direct pharmacologic utility and capacity of pluripotent human embryonic stem cell (hESC) therapy derivatives for human CNS and myocardium regeneration and, thus, have presented the hESC cell therapy derivatives as a powerful pharmacologic agent of cellular entity for a wide range of CNS and heart diseases. The hESC cardiomyocyte cell therapy derivatives by novel small molecule induction provide a large scale of high quality human cardiomyocyte source for myocardium regeneration and, thus, meet the designation of human stem cell therapy products in plasticity, specificity, and stability for commercial development and human trials or first-in-human studies in cardiovascular diseases.

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

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-14 net votes
12 up votes
26 down votes
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Goal 3: Advance Translational Research

Sickle cell disease and fatigue

What factors, other than hemoglobin count, are involved in the extreme fatigue experienced by individuals living with sickle cell disease?

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 :

Many in the sickle cell community report continuous fatigue that interrupts their daily activities in spite of normal, or above baseline, hemoglobin levels

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

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17 net votes
29 up votes
12 down votes
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Goal 2: Reduce Human Disease

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

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

Submitted by (@freddigoldman)

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

Details on the impact of addressing this CQ or CC :

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

Feasibility and challenges of addressing this CQ or CC :

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

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Goal 2: Reduce Human Disease

What is the place of curative therapies in the management of Sickle Cell Disease

Advances in the care of pediatric patients with sickle cell disease ( SCD) have resulted in improved survival to adulthood.However, adulthood is marked by rapid disease progression, impaired quality of life and premature mortality. Hematopoietic cell transplantation(HCT) from matched sibling donor has curative potential, but has been offered mainly to children. Refinements in the conditioning regimen, supportive care, ...more »

Submitted by (@lakshmanankrishnamurti)

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

Details on the impact of addressing this CQ or CC :

To overcome this obstacle to progress in the field, we propose the creation of the funding mechanisms for a multicenter clinical trial consortium which would bring together investigators in field and facilitate study the outcomes of CT for patients with different types of donors and stem cell sources and compare them to outcomes in phenotypically matched controls receiving best available standard of care.Answering the compelling question about the role of CT in the management of SCD has the potential to have a catalytic effect in progress in this field. Patients are are then more likely to receive CT or standard of care at the appropriate time and in the manner in which they are most likely to have a positive outcome. This has the potential to reduce morbidity and premature mortality and in the long run, to decrease the burden of the disease on the healthcare system. The advent of clinical trials of gene therapies for SCD offers the prospect of even greater applicability of curative therapies. Thus, a consortium developed to answer this CQ would serve as a crucial vehicle for providing access to a greater proportion of patient to these personalized curative therapies . Such studies would also be powered to answer the question about who should receive the curative therapy, when they should receive it, and how it would impact their SCD related complications, late effects, survival and quality of life and help families make informed choice appropriate for their situation.

Feasibility and challenges of addressing this CQ or CC :

The increasing applicability and acceptability of HCT for SCD is evidenced by the doubling in the number of such procedures reported to CIBMTR in the decade starting 2001. Refinements in conditioning regimen and supportive care continue to improve outcomes in children and now in adults with SCD undergoing HCT from HLA matched related donors. Recently, HCT from unrelated donors and from haplo-identical donors have further increased the applicability of HCT. Opening of gene therapy trials has further raised the prospect of cure for a greater proportion of patients. These developments are evidence of the feasibility of recruitment to large multi-center comparative trials of SCD and standard of care. Recently, there has been increasing collaboration among investigators in the field with informal consortia being developed by investigators coming together to study HCT for children, adults or HCT from haplo-identical donors. These groups are also increasingly working with SCD hematologists, families and other stakeholders. There is also increasing cross-cutting collaborations with other medical specialists and behavioral and translational scientists Thus, the convergence of several factors described above suggests that the time is fortuitous for a major initiative from the NHLBI to bring investigators together and create the infrastructure that will enable these investigators to seek definitive answers to the challenging question “What is the place of curative therapy in SCD?”.

Name of idea submitter and other team members who worked on this idea : Lakshmanan Krishnamurti, MD, Allistair Abraham MD, John Horan MD and members of the Sickle cell Transplantation and Research Alliance

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141 up votes
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Goal 2: Reduce Human Disease

Transplantation across HLA barriers in aplastic anemia

Allogeneic stem cell transplantation is curative in aplastic anemia with much less intrinsic toxicity than transplantation in hematologic malignancies. The recent BMT-CTN trial demonstrated 97% survival at one year with little subsequent decline. However patients without matched related or unrelated donors have graft-rejection rates of up to 50%. Preliminary data from the Netherlands suggests that anti-thymocyte globulin ...more »

Submitted by (@jantin)

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 use of umbilical cord blood or haploidentical donors has proven effective in patients with hematologic malignancies, but in non-malignant disorders outcomes are limited by graft rejection. Overcoming rejection in this context would be applicable to other non-malignant disorders such as thalassemia, sickle cell anemia, and other congenital disorders of hematopoiesis.

Feasibility and challenges of addressing this CQ or CC :

It will require a large coordinated network like BMT-CTN to obtain sufficient patients studied in a uniform fashion to provide consistent reproducible data. .

Name of idea submitter and other team members who worked on this idea : Joseph Antin

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110 net votes
137 up votes
27 down votes
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Goal 2: Reduce Human Disease

The potency and safety of transfusable red blood cells

Can we identify approaches to improve potency and/or safety of transfusable RBCs? 42 day pre-transfusion storage of RBCs maximizes utilization, while minimizing waste. However, RBCs undergo changes during collection, manipulation and storage that may reduce their potency or safety. Progress in understanding markers that predict transfusion success at the time of collection and with storage remains slow. New technologies ...more »

Submitted by (@nareg.roubinian)

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

Details on the impact of addressing this CQ or CC :

While novel RBC storage methods have been described, the mechanisms underlying their efficacy has not been defined, a step that will be important for further improvements in this area. Some of these methods appear to improve efficacy of the RBC bioenergetic pathways; however, to date there have not been notable advances in reducing cytoskeletal defects common in stored RBCs. The development of new RBC preservation methods that minimize the impact of the storage lesion on specific areas of concern (e.g., diminished oxidation/peroxidation, decreased membrane fragility) is needed.

 

Use of ex vivo generated RBCs is an alternative to conventional donor-derived RBCs which can potentially improve product consistency, reduce the storage lesion, and improve safety. However, advances are needed before this approach is feasible on a large scale. While the development of blood substitutes including blood pharming will likely require more than 3-10 years before it can be ready for the clinic, Blood Pharming from hematopoietic stem/progenitor cells is now technically feasible and the recent development of genome editing methods suggests the exciting possibility of generating GMP compliant “immortal” stem cell sources to produce transfusable RBCs.

Feasibility and challenges of addressing this CQ or CC :

Research should include both pre-clinical and clinical studies to define optimal combinations of known factors preserving red cells (e.g. hypo-osmolarity, energy sources, antioxidants), and the development of methods for RBC pathogen reduction that do not increase the storage lesion.

 

Procedures for generating blood cells from cultured stem/progenitor cells is not currently cost-effective, limiting near term applications to special patient populations such as specific RBC phenotyping of rare donors for chronically transfused patients. Areas of research needed to advance the development of blood substitutes and blood pharming include: (a) new approaches to blood substitutes including artificial oxygen carriers generated from red cell lysates/components or engineered from combinatorial chemico-biological approaches (e.g., derivatization of hemoglobin, encapsidation of modulated oxygen carriers); (b) a better understanding of the biological properties of cultured RBCs with the goal of reducing blood pharming costs; (c) optimizing methods to expand stem cell populations while allowing differentiation to selected clinically relevant blood cell populations at clinically relevant levels; and (d) optimizing methodologies that faithfully replicate embryonic development to develop the cells of interest.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the NHLBI State of the Science in Transfusion Medicine

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31 up votes
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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.

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106 net votes
129 up votes
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Goal 2: Reduce Human Disease

Neurocognitive development and delays in sickle cell disease

Are neurocognitive developmental delays significantly present in children and adolescents living with sickle cell disease? What effect do these delays have on the overall morbidity associated with sickle cell disease?

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 :

Conversations among the sickle cell population are increasingly focusing on mental health, neuropsycology as it relates to mental health, and the need to develop community life skills and personal development.

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

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30 net votes
41 up votes
11 down votes
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