Big data are used in the pursuit of precision medicine in the general population. Applying these tools to patients with sickle cell disease (SCD) is essential for ensuring that they receive the most appropriate customized therapy for their disease. For these tools to be applied, there must be a large number of willing, fully phenotyped participants in collaborative registries. Working collaboratively to respond to unmet clinical needs and the lack of a large multisite registry, SCD providers at multiple sites developed The Globin Regional Data and Discovery (GRNDaD) registry. The specific goals of GRNDaD are to (1) prospectively obtain high-quality curated data on the evolving population affected by SCD; (2) improve adherence to guideline-based care; (3) provide a platform for ongoing quality improvement across sites; (4) allow for real-time investigation of therapies, and collaborate broadly to address research questions using GRNDaD as a shared platform. GRNDaD’s current strength lies in the generous participation of people living with SCD, collaborative investigators, and the opportunity to conduct quality improvement activities across a large number of sites. GRNDaD will serve as the data collection tool for the Health Resources and Services Administration Sickle Cell Treatment Demonstration Program and for the newly established National Alliance for Sickle Cell Centers (https://www.sicklecellcenters.org/). GRNDaD is a robust collaborative registry that providers and researchers will use to identify genetic markers that will help predict outcomes and lead to a better understanding of the natural history of SCD in the modern era of novel therapies.

Big data are used in the pursuit of precision medicine in the general population. Applying these tools to patients with sickle cell disease (SCD) is essential for ensuring that they receive the most appropriate customized therapy for their disease. For these tools to be applied, there must be a large number of willing, fully phenotyped participants in collaborative registries. Working collaboratively to respond to unmet clinical needs and the lack of a large multisite registry, SCD providers at multiple sites developed The Globin Regional Data and Discovery (GRNDaD) registry. The specific goals of GRNDaD are to (1) prospectively obtain high-quality curated data on the evolving population affected by SCD; (2) improve adherence to guideline-based care; (3) provide a platform for ongoing quality improvement across sites; (4) allow for real-time investigation of therapies, and collaborate broadly to address research questions using GRNDaD as a shared platform. GRNDaD’s current strength lies in the generous participation of people living with SCD, collaborative investigators, and the opportunity to conduct quality improvement activities across a large number of sites. GRNDaD will serve as the data collection tool for the Health Resources and Services Administration Sickle Cell Treatment Demonstration Program and for the newly established National Alliance for Sickle Cell Centers (<a href="https://www.sicklecellcenters.org/" rel="nofollow" target="_blank">https://www.sicklecellcenters.org/</a>). GRNDaD is a robust collaborative registry that providers and researchers will use to identify genetic markers that will help predict outcomes and lead to a better understanding of the natural history of SCD in the modern era of novel therapies.

GRNDaD: big data and sickle cell disease 

Sickle cell disease (SCD) is an inherited blood condition resulting from abnormal hemoglobin production. It is one of the most common genetic diseases in the world. The clinical manifestations are variable and range from recurrent acute and debilitating painful crises to life-threatening pulmonary, cardiovascular, renal, and neurologic complications. The only curative treatment of SCD at this time is bone marrow transplantation (also called hematopoietic stem cell transplantation) using healthy blood stem cells from an unaffected brother or sister or from an unrelated donor if one can be identified who is a match in tissue typing. Unfortunately, only a minority of patients with sickle cell has such a donor available. The use of autologous hematopoietic stem cells and alternative types of genetic modifications is currently under study in clinical research trials for this disease. The approaches include the use of viral vectors to express globin genes that are modified to prevent sickle hemoglobin polymerization or to express interfering RNAs to “flip the switch” in adult red cells from adult β-sickle hemoglobin to fetal hemoglobin using a physiologic switch, and several gene editing approaches with the goal of inducing fetal hemoglobin or correcting/modifying the actual sickle mutation. In this audio review, we will discuss these different approaches and review the current progress of curative therapy for SCD using gene therapy.

Investigational curative gene therapy approaches to sickle cell disease 

The prospect of a clinical strategy using an adeno-associated virus (AAV) vector for expression of therapeutic levels of factor VIII (FVIII) has been highly desirable. This was initially anticipated by promising data from clinical studies on AAV5-FVIII in men with severe hemophilia A. However, long-term follow-up showed a unique efficacy concern on the sustainability and durability derived from a continuous decline in the FVIII transgene levels starting 1 year after vector injection through year 5. Additional follow-up of early-phase studies and outcomes of an ongoing phase 3 study will likely provide evidence on the feasibility of this approach. Here, the potential underlying mechanisms of the FVIII declining levels, together with the revision of several unique early and late onset findings, are discussed. The lack of long-term preclinical studies in large animal models prevents the firm conclusion that FVIII levels decline was unexpected. It is possible that the combination of vector manufacturing platform and dose, accompanied with ectopic expression of supraphysiologic levels of FVIII at short-term follow-up, may all contribute to the sustainability and durability of the transgene levels. Notably, vector readministration to further improve the FVIII levels is not feasible at this time. Thus, the need of a one-and-done AAV strategy to achieve sustain FVIII levels of expression is sine qua non to impact favorably the disease phenotype.

Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet?

The availability of novel nonfactor therapeutics is revolutionizing the management of hemophilia in individuals with inhibitory antibodies, as well as making prophylaxis more convenient even in the absence of inhibitors. Unfortunately, the use of these products has been associated with thrombotic events that are not typically seen with factor replacement. These are primarily seen when a patient on a nonfactor therapy experiences breakthrough bleeding and concomitantly receives another hemostatic agent. This video addresses thrombotic complication in 3 nonfactor products: (1) emicizumab, a bispecific antibody that mimics the cofactor activity of factor VIII; (2) fitusiran, an small interfering RNA that knocks down synthesis of antithrombin; and (3) concizumab, an antibody that blocks inhibition of factor Xa by tissue factor pathway inhibitor. The latter 2 agents were developed on the premise that hemostasis in hemophilia could be “rebalanced” by reducing the levels of anticoagulant activity to compensate for the defect in procoagulant activity. Each of these approaches increases peak levels of thrombin achieved in assays on plasma from treated subjects and reduces bleeding rates in individuals with or without inhibitors. However, we do not yet have a good mechanistic model for precisely how these approaches affect hemostasis in vivo. It is not only the total amount of active thrombin produced that determines the effectiveness of hemostasis but also how thrombin generation is regulated. Therefore, it is currently difficult to predict how these new agents will interact with other perturbations or therapeutic manipulations of the coagulation system.

Thrombosis and novel hemophilia therapies: the fine line between clotting and bleeding 

Amy Shapiro discusses the recent approval of concizumab for the treatment of patients with hemophilia. This novel subcutaneous homeostatic rebalancing agent has proven to be useful for the treatment of patients with hemophilia A and B, and we hope you find this talk to be useful to understand it.

Concizumab: a novel anti-TFPI therapeutic for hemophilia

Allogeneic hematopoietic stem cell transplantation (HCT) is curative in many patients with advanced hematopoietic malignancies. Donor T cells not only facilitate engraftment and protect against opportunistic pathogens and residual disease, but can also cause graft-versus-host disease (GVHD), with significant morbidity and mortality. 

Allogeneic hematopoietic stem cell transplantation (HCT) is curative in many patients with advanced hematopoietic malignancies. Donor T cells not only facilitate engraftment and protect against opportunistic pathogens and residual disease, but can also cause graft-versus-host disease (GVHD), with significant morbidity and mortality.

Naive T-cell depletion in stem cell transplantation

The high incidence of thromboembolic disease, and in particular venous thromboembolism (VTE), has emerged as an important consideration in hospitalized and critically ill patients with coronavirus disease 2019 (COVID-19). 

The high incidence of thromboembolic disease, and in particular venous thromboembolism (VTE), has emerged as an important consideration in hospitalized and critically ill patients with coronavirus disease 2019 (COVID-19).

The management of venous thromboembolism in hospitalized patients with COVID-19 

The treatment of hemophilia, which has undergone many transformative changes over the past 60 years, is poised for yet another disruptive change: the use of gene therapy to produce functional cures in some persons with hemophilia A or B. 

The treatment of hemophilia, which has undergone many transformative changes over the past 60 years, is poised for yet another disruptive change: the use of gene therapy to produce functional cures in some persons with hemophilia A or B.

Gene therapy for hemophilia: anticipating the unexpected

The changing landscape of anticoagulation in cancer-associated thrombosis 

The changing landscape of anticoagulation in cancer-associated thrombosis

The changing landscape of anticoagulation in cancer-associated thrombosis 

TA-TMA: state of the art for diagnosis and treatment by Blood Advances Talks

TA-TMA: state of the art for diagnosis and treatment

Blood Advances, a Journal of the American Society of Hematology, provides an open international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology and related sciences.Music for Blood Advances Talks is preformed by the Art Topilow Trio

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Inherited predisposition to myeloid malignancies

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Daily light-and-darkness onset regulates mouse hematopoietic stem cells

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Extended therapy for unprovoked venous thromboembolism: when is it indicated?

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Antiplatelet therapy in the management of atherothrombosis: recent clinical advances

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Challenges facing the benign hematology physician-scientist workforce

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Choosing for whom to recommend allogeneic transplantation for AML in CRL

Catalyzing innovation in clinical trial design and analysis at NHLBI by Blood Advances Talks

Catalyzing innovation in clinical trial design and analysis at NHLBI

ITP and thrombosis: an intriguing association by Blood Advances Talks

ITP and thrombosis: an intriguing association

The current therapeutic landscape of FLT3 inhibitors by Blood Advances Talks

The current therapeutic landscape of FLT3 inhibitors

Blood Advances, a Journal of the American Society of Hematology, provides an open international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology and related sciences. Music for Blood Advances Talks is preformed by the Art Topilow Trio

Blood Advances Talks

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Venetoclax: a primer

The Direct Oral Anticoagulants – can we finally stop using rat poison? by Blood Advances Talks

The Direct Oral Anticoagulants – can we finally stop using rat poison?

The Lucky Iron Fish: a simple solution for iron deficiency by Blood Advances Talks

The Lucky Iron Fish: a simple solution for iron deficiency

Impact of the ICAL on the treatment of acute leukemia by Blood Advances Talks

Impact of the ICAL on the treatment of acute leukemia

The Best Multi-Part Documentaries, with documentaries on Obama, Federer vs Nadal, the making of Star Wars, Netflix vs Blockbuster and more. Add episodes you're interested into your queue below!

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