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Towards Transformative Therapies for Sickle Cell Disease

Available via


Towards Transformative Therapies for Sickle Cell Disease

Tuesday, October 24, 2017

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York, USA

Presented By

Biochemical Pharmacology Discussion Group

The New York Academy of Sciences


Sickle Cell Disease (SCD) is a debilitating blood disorder with high mortality rates, yet to date only a single therapy for the disease has been approved by the FDA. Markedly, improved insight into the complex pathophysiology of SCD has led to the recent development of diverse approaches for treatment, including inhibition of hemoglobin polymerization, prevention and treatment of vaso-occlusive events, and disease corrective gene therapy approaches. This symposium will discuss these recent developments highlighting key biological mechanisms of disease and reviewing relevant clinical science around SCD, while underscoring the importance of the patient experience.

Call for Abstracts

Abstract submissions are invited for a poster session, and two abstracts will be selected for short talks. For complete submission instructions, please visit our online portal. The deadline for abstract submission is September 8, 2017.


Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow
Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow


October 24, 2017

8:30 AM

Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks


Sonya Dougal, PhD
The New York Academy of Sciences
Patrick Hines, MD, PhD
Functional Fluidics & Children's Hospital of Michigan

Session 1: The Patient Perspective and Patient Reported Outcomes

9:15 AM

Patient's Perspective


Marie Ojiambo
Sickle Strong Initiative
9:45 AM

Transformative Pain Therapy in Sickle Cell Disease


Wally Smith, MD
Virginia Commonwealth University Medical Center

Pain in sickle cell disease (SCD) is more often chronic than previously thought, though acute pain is still the hallmark of the disease. Both are undertreated. In adults and even in children, the quantity and severity of SCD pain may be vastly underestimated, because most of the “iceberg” of chronic SCD pain is “submerged” at home. The implications of this iceberg phenomenon are significant for pain treatment. Earlier, clinicians focused on adequate treatment of acute pain in SCD. It is still a challenge. Appropriate acute care triage of SCD crises to a high rather than low priority, coupled with individualized pain plans, can ensure timely, more effective acute therapy, and likely save hospitalizations. But a comprehensive focus requires remittive and palliative therapies for chronic pain treated at home. Three issues dominate the chronic pain debate. First, should opioids be the mainstay of chronic palliative SCD therapy? Second, does preventing sickling, preventing vasculopathy from SCD, preventing organ failure, or even curing SCD with bone marrow transplant, result in improvement of acute or chronic subjective pain? Third, do we have enough information to justify use of therapies intended for neuropathic or central pain, present in diseases as diverse as irritable bowel syndrome, temporo-mandibular joint syndrome, fibromyalgia, chronic pelvic pain, and rheumatoid arthritis?

Transformative SCD pain therapy would feature an array of interventions for acute and chronic SCD pain, and a full classification of pain phenotypes which qualified patients for acute and chronic pain palliative and remittive interventions.

10:15 AM

A Natural History Study to Evaluate Longitudinal Changes in Sickle Cell Disease


Debra Pittman, PhD
10:45 AM

Networking Coffee Break

Session 2: Vascular Pathology of Sickle Cell Disease

11:15 AM

Therapeutics in Development to Treat Sickle Cell Disease Vasco-Occlusive Events


Deepa Manwani, MD
The Children's Hospital at Montefiore, Albert Einstein College Of Medicine
11:45 AM

A Phase II, Randomized, Placebo-Controlled Trial of Crizanlizumab in Sickle Cell Disease


Kenneth I. Ataga, MD
University of North Carolina at Chapel Hill
12:15 PM

Enucleation and Beta-Globin Expression in Induced Red Blood Cells: A Platform to Model Sickle Cell Anemia


Tolulope O Rosanwo, BA
Boston Children's Hospital

Human induced pluripotent stem cells (hiPSCs) hold promise for both disease modeling and the development of novel therapeutic treatments for sickle cell anemia (SCA). Such models are practical systems to screen new drug therapies and to examine the effects of gene editing. hiPSCs can theoretically produce all cell types including erythroid cells. However, in vitro modeling of SCA with reprogrammed cells has been limited by their inability to differentiate into beta globin-expressing, enucleated erythroid cells. Here, we propose strategies to produce improved in vitro models of SCA using these cell types. We derived hiPSCs from sickle cell patients with hemoglobin SS disease seen at our hematology clinic at Boston Children’s Hospital. Using a cocktail of transcription factors promoting self-renewal and multi-potentiality expressed under the control of a doxycycline-regulated promoter (Erg, HoxA9, RORa, Sox, Myb) we generated conditionally immortalized hematopoietic cell lines that serve as a renewable source of robust erythroid progenitors in vitro. Concurrently, we further improved the in vitro differentiation protocols described to generate 30-40% beta-globin-expressing, erythroid cells with an enucleation rate of 20-50%. In future studies, we hope to further improve in vitro beta globin expression via genetic/epigenetic modulation of the globin loci. Such a sickling platform will permit the employment of hiPSCs to test the therapeutic hypothesis that genetic manipulation of BCL11A, a master regulator of fetal hemoglobin (HbF) expression, will ameliorate sickling. The generation of hiPSC-SCA models will be critical in broadening the current understanding of the molecular mechanisms of this disease, the development of improved pharmacological treatments and a future of autologous cell therapy for the cure of SCA.

12:20 PM

Establishment of Steady State Adhesion Indices in Sickle Cell Disease: Clinical Application of a Standardized Adhesion Bioassay


Patrick Hines, MD, PhD
Functional Fluidics & Children's Hospital of Michigan

Erythrocyte adhesion contributes to sickle cell disease severity. We have developed a standardized microfluidic flow-based adhesion assay to measure erythrocyte adhesion indices and longitudinal variability. Blood samples were collected from heterozygote (AS; n=4) and normal (AA; n=10) controls and SCD subjects (n=35; 13-48 yrs, avg 25.9yrs) at steady state as verified by an electronic patient reported outcome (ePRO) tool. Blood was drawn every 3 weeks for 3 months (AA and AS controls)/6 months (SCD patients). The standardized adhesion assay was performed by flowing 30mL of whole blood over immobilized VCAM-1, followed by quantifying the adherent cells (adhesion index; cells/mm2). Correlations between steady state adhesion and clinical laboratory parameters were assessed using the Spearman rank correlation coefficient. Steady state adhesion varied from sample-to-sample (n=292; mean = 353.5 ± 236.3; median = 294 cells/mm2). Steady state adhesion had statistically significant positive correlations with white blood cell count (WBC; r=0.239; p<0.0001), C-reactive protein (CRP; r=0.254; p<0.0001), platelet count (r=0.124; p=0.0357), and reticulocyte percentage (r=0.5108; p<0.0001), and statistically significant negative correlations with hematocrit (r=-0.1599; p=0.0067) and fetal hemoglobin (r=-0.485; p<0.0001). Finally, we demonstrated a statistically significant correlation between the historical disease severity of each patient and steady state adhesion. Steady-state adhesion indices and longitudinal adhesion variability can serve as a basis to further study adhesion as a biomarker for sickle cell disease severity, a platform to assess preclinical response to SCD therapy, and monitor response to therapy.

12:25 PM

Networking Lunch and Poster Viewing

Session 3: Hemoglobin Reprogramming

2:00 PM

The Regulation of Fetal Hemoglobin Expression


Vijay G. Sankaran MD, PhD
Boston Children's Hospital, Harvard Medical School

The transition from the predominant production of fetal hemoglobin (HbF) to adult hemoglobin shortly after the time of birth in humans has been extensively studied, given that elevated production of HbF can ameliorate clinical symptoms in both sickle cell disease and β-thalassemia. A number of factors regulating HbF production have been identified through unbiased human genetic studies of both common and rare variation, including BCL11A, KLF1, and MYB. However, the mechanisms underlying the developmental regulation of HbF expression and the regulation of factors such as BCL11A in this process is unknown. In this presentation, we will discuss recent work from our group using both human genetic observations and functional studies in human erythroid cells, which has allowed us to identify new pathways regulating this process. Specifically, we will discuss new insight into the regulation of BCL11A protein expression during human ontogeny. While BCL11A is robustly expressed in adult erythroid cells, it is expressed at significantly lower levels in cord blood and fetal liver erythroid cells from humans. We have investigated the underlying mechanisms by which these differences arise during human development. This new insight into the regulation of BCL11A production during human hematopoiesis suggests new therapeutic avenues to reduce BCL11A expression and thereby induce HbF synthesis in patients with sickle cell disease and β-thalassemia.


2:30 PM

Disrupting a BCL11A Enhancer with Zinc Finger Nucleases for the Treatment of Sickle Cell Disease and β-Thalassemia


Dana Levasseur, PhD
3:00 PM

Networking Coffee Break

Session 4: Novel Therapeutic Approaches

3:30 PM

GBT440: a Novel Sickle Hemoglobin Polymerization Inhibitor


Brahm Goldstein, MD, MCR
Global Blood Therapeutics
4:00 PM

Lentiviral Vector Gene Therapy for Sickle Cell Disease


Philip D. Gregory, D. Phil
4:30 PM

Closing Remarks and F1000 Poster Prize Presentation


Ellis Neufeld, MD, PhD
Boston Children’s Hospital
4:45 PM

Networking Reception and Poster Viewing

5:45 PM