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60 Minutes airs: Gene Therapy for Sickle Cell Disease

Could gene therapy cure sickle cell anemia?

An NIH clinical trial is ushering in a genetic revolution as an innovative type of gene therapy is used to attempt to cure sickle cell anemia. Dr. Jon LaPook reports. Air Date: Mar 10, 2019

Researchers at Dana-Farber/Boston Children’s optimize gene editing for SCD and beta thalassemia

New strategy for editing blood stem cells is more efficient and targeted – Researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the University of Massachusetts Medical School have developed a strategy to treat two of the most common inherited blood diseases — sickle cell disease and beta thalassemia — applying CRISPR-Cas9 gene editing to patients’ own blood stem cells. Described this week in Nature Medicine and in a January report in the journal Blood, their approach overcomes prior technical challenges, editing blood stem cells more efficiently than in the past.

The two studies show that the gene-edited cells generate genetically corrected red blood cells producing functional hemoglobin.

“We think our work defines a strategy that could lead to the cure of common hemoglobin disorders,” says Daniel Bauer, MD, PhD, an attending physician with Dana-Farber/Boston Children’s and a senior author on both papers. “Combining gene editing with an autologous stem-cell transplant could be a therapy for sickle-cell disease, beta-thalassemia and other blood disorders.”

Together, sickle cell disease and beta-thalassemia affect 332,000 conceptions or births worldwide each year, according to the World Health Organization. Both diseases involve mutations in the gene for beta globin protein. In beta-thalassemia, the mutations prevent red blood cells from producing enough of the oxygen-carrying hemoglobin molecule, leading to anemia. In sickle cell disease, the mutation causes hemoglobin to change shape, distorting red blood cells into stiff “sickle” shapes that block up blood vessels.

More efficient editing

The Nature Medicine study used CRISPR-Cas9 technology, in particular a Cas9 protein modified by a team led by Scot Wolfe, PhD at UMass Medical School, to optimize gene editing. In previous attempts to edit the genomes of human blood stem and progenitor cells, the efficiency, specificity and long-term stability of the edits once the cells engraft in the bone marrow have varied. The new technique improves the targeting and durability of the edits.

“Efficient editing of the blood stem cell population — ideally at rates approaching 100 percent — is critical to achieve a durable therapeutic effect for patients,” says Wolfe, a professor in the Department of Molecular, Cell and Cancer Biology at UMass Medical School. “Progress toward this goal has been advancing through the contributions of multiple laboratories in the scientific community. My research team, in collaboration with the Bauer laboratory, focused on improving the efficiency of delivery and nuclear entry of the CRISPR-Cas9 technology to achieve nearly complete therapeutic editing of the entire blood stem cell population.”

Bauer’s team used the strategy to make a highly targeted edit. Previous work at Boston Children’s had showed that inactivating a gene called BCL11A allows red blood cells to keep producing a fetal form of hemoglobin even after birth. Fetal hemoglobin doesn’t sickle and can stand in for defective “adult” hemoglobin. More recently, Bauer found a safer target: a genetic enhancer of BCL11A that is active only in red blood cells.

“With our new very efficient protocol, we can edit the BCL11A enhancer in nearly all blood stem cells we collect, overcoming some of the technical challenges of editing these cells,” says Bauer. “In our experiments, more than 95 percent of copies of the enhancer sequence were changed in a way we expect would be therapeutic.”

The strategy enabled mice carrying blood stem cells from patients with sickle cell disease to produce red blood cells with enough fetal hemoglobin to prevent cell sickling. The team showed that the gene-edited cells, infused back into the bloodstream, engrafted in the bone marrow and produced genetically corrected red blood cells. Later, when blood stem cells were isolated from these mice and transplanted into other mice, the cells engrafted again, still carrying the therapeutic gene changes.

Applied to blood stem cells from patients with beta-thalassemia, the same strategy restored the normal balance of the globin chains that make up hemoglobin.

The other study, published in Blood, used a similar gene editing protocol to target forms of beta-thalassemia that involve splicing mutations — errors in bits of DNA near the beta-globin gene that change how the gene is read out to assemble beta-globin protein. In this study, nine patients with beta thalassemia donated their cells, which were manipulated in a dish. For some patients, the UMass team produced a different enzyme, Cas12a, to more effectively target their mutations. The CRISPR system efficiently made edits and restored normal splicing of the beta-globin protein in blood cells from each of the patients.

Setting the stage for a clinical trial

The investigators are taking steps to take their BCL11A enhancer editing strategy to the clinic. They are developing a clinical-grade, scaled up protocol for cell product manufacturing, and performing safety studies necessary for regulatory approval from the FDA. They plan to seek funding from the National Heart, Lung and Blood Institute’s Cure Sickle Cell initiative to launch a clinical trial in patients.



Table of Contents


1. Sickle Cell and the Simplifications of Science

2. Why Genes are not “For” Sickle Cell

3. A Social History of Sickle Cell Part I: Sickle Cell and Malaria

4. A Social History of Sickle Cell Part II: Politics and Molecules

5. Sickle Cell and Athletes

6. Sickle Cell and Deaths in State Custody

7. Ethnicity and Sickle Cell

8. Genetic Carriers and Antenatal Screening

9. Newborn Screening

10. SCD and the Social Model of Disability

11. Sickle Cell and Social Policy: The Case of SCD and Schools


Sickle Cell Fellowship, Comprehensive Sickle Cell Center

St. Jude Children’s Research Hospital, Memphis, TN.

The Comprehensive Sickle Cell Center at St. Jude is one the largest sickle cell disease programs in the country, caring for approximately 900 children with sickle cell disease each year. Our partnerships with Methodist University Hospital and the University of Tennessee connects our faculty and fellows to an adult sickle cell population of approximately 350 adults. Operating as part of the Comprehensive Sickle Cell Center, the St. Jude-Methodist Sickle Cell Disease Transition clinic ensures the appropriate transition of adolescents to adult health care for ongoing management of this complex chronic disease. The clinic serves as a national model for other programs aiming to improve outcomes of this disease.

St. Jude announces a one-year sickle cell fellowship program starting July 2019. Supported by an outstanding multidisciplinary team, the program focuses on providing patient centered/family focused care to patients. The program aims on training innovative leaders with expertise in clinical management of disease in both pediatric and adult patients. With mentorship from by some of the nationally recognized leaders in the field, the fellow will have an opportunity to participate in clinical research and present at local and national meetings.

Eligible applicants will have completed training in pediatric hematology/oncology, adult hematology/oncology, adult hematology, internal medicine, family medicine or medicine/pediatrics. Interested candidates should send a copy of their CV, a personal statement, and three letters of recommendation to the program directors at the emails below.

Jane Hankins, MD:

Latika Puri, MD:

Articles in the medical literature

1. Am J Hematol. 2019 Mar 27. doi: 10.1002/ajh.25471. [Epub ahead of print] Normal Saline Bolus Use in Pediatric Emergency Departments is Associated with Worse Pain Control in Children with Sickle Cell Anemia and Vaso-occlusive Pain. Carden MA1, Brousseau DC2, Ahmad FA3, Bennett J4, Bhatt S5, Bogie A6, Brown K7, Casper TC8, Chapman LL9, Chumpitazi CE10, Cohen D11, Dampier C12,13, Ellison AM14, Grasemann H15, Hickey RW16, Hsu LL17, Leibovich S18, Powell E19, Richards R8, Sarnaik S20, Weiner DL21, Morris CR12,13; Sickle Cell Disease Arginine Study Group and the Pediatric Emergency Care Applied Research Network (PECARN). Abstract Vaso-occlusive pain events (VOE) are the leading cause of emergency department (ED) visits in sickle cell anemia (SCA). This study assessed the variability in use of intravenous fluids (IVFs) and the association of normal saline bolus (NSB) on pain and other clinical outcomes in children with SCA presenting to pediatric emergency departments (PED) with VOE. Four-hundred charts of children age 3-21 years with SCA/VOE receiving parenteral opioids at 20 high-volume PEDs were evaluated in a retrospective study. Data on type and amount of IVFs used were collected. Patients were divided into 2 groups: those who received NSB and those who did not. The association of NSB use on change in pain scores and admission rates was evaluated. Among 400 children studied, 261(65%) received a NSB. Mean age was 13.8±4.9 years; 46% were male; 92% had hemoglobin-SS. IVFs (bolus and/or maintenance) were used in 84% of patients. Eight different types of IVFs were utilized and IVF volume administered varied widely. Mean triage pain scores were similar between groups, but improvement in pain score from presentation-to-ED-disposition was smaller in the NSB group (2.2 vs. 3.0, p=0.03), while admission rates were higher (71% vs. 59%, p=0.01). Use of NSB remained associated with worse final pain scores and worse change in pain scores in our multivariable model. In conclusion, wide variations in practice utilizing IVFs are common. NSB is given to >50% of children with SCA/VOE, but is associated with worse pain control; a controlled prospective trial is needed to determine causality. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
PMID: 30916794
2. Transfus Apher Sci. 2019 Mar 13. pii: S1473-0502(19)30019-9. doi: 10.1016/j.transci.2019.03.006. [Epub ahead of print] Red blood cell exchange in children and adolescents with sickle cell disease. Merlin E1, Hequet O2, Kanold J3. Abstract Automatic red blood cell exchange i.e. using devices (RBCX) has become a standard therapy to remove abnormal red blood cells (RBC) in adults and children affected by sickle cell disease (SCD). This treatment is performed both in emergency to treat acute complications and through a regular program of RBCX to prevent the recurrence of complications. However, small children, i.e. those with a low body weight, height and total blood volume, are at risk of relative hypovolemia and metabolic complications during the procedure. Moreover, the peripheral venous access is limited among young children, which requires alternative short- or long-term venous access. These two main limiting factors necessitate adaptations of the procedures and subsequent monitoring during and after the sessions. However, performing RBCX in children requires other adaptations and cautions that must be considered. Our review summarizes the limits, safety precautions and the adaptations of the techniques to ensure RBCX in children. Copyright © 2019. Published by Elsevier Ltd.
PMID: 30914240
3. Nat Med. 2019 Mar 25. doi: 10.1038/s41591-019-0401-y. [Epub ahead of print] Highly efficient therapeutic gene editing of human hematopoietic stem cells. Wu Y1,2,3,4, Zeng J1,2,3, Roscoe BP5, Liu P5, Yao Q1,2,3,6,7, Lazzarotto CR8, Clement K6,7, Cole MA1,2,3, Luk K5, Baricordi C1,2,3,9, Shen AH1,2,3, Ren C1,2,3, Esrick EB1,2,3, Manis JP1,2,3, Dorfman DM10,11, Williams DA1,2,3, Biffi A1,2,3,9, Brugnara C1,2,3, Biasco L1,2,3,9,12, Brendel C1,2,3,9, Pinello L6,7, Tsai SQ8, Wolfe SA5, Bauer DE13,14,15. Abstract Re-expression of the paralogous γ-globin genes (HBG1/2) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, α2γ2)1. Previously, we and others have shown that core sequences at the BCL11A erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but are dispensable in non-erythroid cells2-6. CRISPR-Cas9-mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs). Here, we demonstrate that Cas9:sgRNA ribonucleoprotein (RNP)-mediated cleavage within a GATA1 binding site at the +58 BCL11A erythroid enhancer results in highly penetrant disruption of this motif, reduction of BCL11A expression, and induction of fetal γ-globin. We optimize conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. HSCs preferentially undergo non-homologous compared with microhomology-mediated end joining repair. Erythroid progeny of edited engrafting SCD HSCs express therapeutic levels of HbF and resist sickling, while those from patients with β-thalassemia show restored globin chain balance. Non-homologous end joining repair-based BCL11A enhancer editing approaching complete allelic disruption in HSCs is a practicable therapeutic strategy to produce durable HbF induction.
PMID: 30911135
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4. Pediatr Blood Cancer. 2019 Mar 25:e27722. doi: 10.1002/pbc.27722. [Epub ahead of print] Implementation of an educational intervention to optimize self-management and transition readiness in young adults with sickle cell disease. Calhoun CL1,2, Abel RA3, Pham HA4, Thompson S5, King AA1,2,3. Abstract BACKGROUND: The transition from the pediatric setting to adult care is a well-described period of morbidity and mortality for persons with sickle cell disease (SCD). We sought to measure the feasibility and effectiveness of providing skill-based educational handouts on improving self-management and transition readiness in adolescents with SCD. METHODS: This was a single-center study in which participants completed a self-assessment, the Adolescent Autonomy Checklist (AAC), to assess transition readiness and self-management skills at baseline. After results were reviewed by the study coordinator, participants were provided with skill-based handouts on noted areas of deficit. The AAC was subsequently completed at a follow-up visit. All data were stored electronically and transferred into SAS for statistical analyses. RESULTS: Sixty-one patients completed the AAC at baseline and postintervention. At baseline, patients reported needing the most help with skills in money management, living arrangements, vocational skills, and emergency and healthcare skills. Postintervention, statistically significant improvements (P < 0.05) occurred in skills related to laundry, housekeeping, healthcare, and sexual development. A regression model exploring the time to follow-up showed that most improvements could not be attributed to maturation alone. CONCLUSION: This study showed that educational handouts are a readily implementable and well-accepted intervention among adolescents with SCD who identify challenges with skills necessary to successfully transition to adult care. Distinguishing which transition needs are best improved with this type of intervention will help to strengthen the multidisciplinary approach necessary to support adolescents and young adults with SCD as they matriculate to adult care. © 2019 Wiley Periodicals, Inc.
PMID: 30907500
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5. J Neuroradiol. 2019 Mar 20. pii: S0150-9861(19)30200-7. doi: 10.1016/j.neurad.2019.03.001. [Epub ahead of print] Intracranial aneurysms in Sickle Cell Disease: Aneurysms characteristics and modalities of endovascular approach to treat these patients. Gallas S1, Tuilier T2, Ebrahiminia V3, Bartoluci P4, Hodel J2, Gaston A2. Abstract INTRODUCTION: The neurological complications of Sickle Cell Disease (SCD) include cerebral infarction and haemorrhage with rarely subarachnoid haemorrhage due to cerebral aneurysms. MATERIALS AND METHODS: In our interventional department, working with SCD referral department, we reported our experience concerning management of adult’s patients with cerebral aneurysms. We identified 26 adults with 48 intracranial aneurysms documented by imaging. RESULTS: 18 patients, with 26 cerebral aneurysms were treated by endovascular approach for their aneurysms. No patient was treated by surgical way in our institution. 50% of patients had multiple aneurysms. Locations of aneurysms treated were typical with 70 % of cerebral anterior artery and 30 % of posterior artery. Three patients suffered from subarachnoid haemorrhage. Two procedure-related complications occurred during the treatment: one thrombo-embolic event with good recovery after medical treatment and one aneurismal perforation leading to the death of patient. Hypercoagulability is a major specific risk in SCD and use of permanent device as stent of flow diverter should be discussed to prevent complications. CONCLUSION: Endovascular management of these aneurysms seems to be a good alternative to treat these patients, with stability of occlusion at follow-up. Copyright © 2019. Published by Elsevier Masson SAS.
PMID: 30904450
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6. Pediatr Blood Cancer. 2019 Mar 22:e27721. doi: 10.1002/pbc.27721. [Epub ahead of print] Hydroxyurea use among children with sickle cell anemia. Reeves SL1,2, Jary HK1, Gondhi JP1, Raphael JL3, Lisabeth LD2,4, Dombkowski KJ1.. Abstract This study describes hydroxyurea use among children ages 1 to 17 with sickle cell anemia (SCA) enrolled in at least one year of Medicaid in six states from 2005 to 2012. Administrative claims were used to summarize the number of days’ supply of hydroxyurea dispensed by state and year. A total of 7963 children with SCA contributed 22 424 person-years. Among person-years with greater than 30 days of hydroxyurea, only 18% received at least 300 days of hydroxyurea, which varied by state. Following updated recommendations for all children with SCA to be offered hydroxyurea, strategies to increase hydroxyurea adherence among this population are needed. © 2019 Wiley Periodicals, Inc.
PMID: 30900800
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7. J Pediatr Hematol Oncol. 2019 Apr;41(3):e141-e145. doi: 10.1097/MPH.0000000000001377. Nutritional Status, Nutrient Intake, and Food Diversity Among Children With Sickle Cell Anemia. Botelho EC1, Mataratzis PSR1, Lino DL1, de Oliveira AN2, Bezerra FF1, Dos Santos Barbosa Brito F1, Citelli M1, Cople-Rodrigues CDS3. Abstract Children with sickle cell anemia (SCA) often exhibit nutritional deficiencies and are at high risk of dying before the age of 5 years. Ensuring adequate nutrition is a critical part of health care for such children. This study aimed to investigate the association between nutritional status, nutrient intake, and food diversity in children with SCA. A descriptive cross-sectional study was conducted on 74 children with SCA, between 24 and 71 months of age. Anthropometric measurements, food and nutrients consumption were determined. The prevalence of low weight, stunting, and overweight/obesity were 16.2%, 35.1%, and 16.2%, respectively. Mean folic acid intake was low (49.05%±51.22%), whereas the intakes of protein (426.71%±171.93%), retinol (292.97%±403.88%), phosphorus (204.55%±151.35%), magnesium (233.02%±151.14%), iron (250.76%±165.81%), and zinc (243.21%±148.40%) were high. The dietary phosphorus/protein ratio was high for 31.1% of the children, and 44.6% of the children had low dietary diversity score. No correlation was found between food diversity, nutrient adequacy, and nutritional status. Despite the adequacy of the intake of most micronutrients, diet quality was inadequate, constituting mainly ultraprocessed foods. Knowing the food consumption pattern of these children enables a more resolute nutritional intervention.
PMID: 30897609
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8. J Pain Palliat Care Pharmacother. 2019 Mar 21:1-7. doi: 10.1080/15360288.2019.1577938. [Epub ahead of print] Comparison of Parenteral Opioid Dosing in Adult Sickle Cell Disease Patients With Vaso-occlusive Crisis. Shah SP, Twilla JD, Kemp L, Phelps GL, Reaves A. Abstract Sickle cell disease (SCD) is a chronic condition characterized by multiple vaso-occlusive complications, including acute pain crisis. The mainstay of treatment for patients presenting with vaso-occlusive crisis (VOC) is pain control and adequate hydration. Currently, there are no studies to determine an optimal pain control regimen in adult SCD patients. The main objective of this study is to evaluate whether outcomes differ in patients with VOC based on pain management treatment modality. A retrospective review of admissions with a primary diagnosis of VOC admitted to our facility was conducted. The primary outcome was to compare the average length of stay (LOS) in patients treated with intermittent injection (INT) or patient-controlled analgesia (PCA). Secondary outcomes assessed included 30-day readmission, treatment failure, and impact on pain scores. Of 302 admissions screened, 150 met inclusion criteria (INT: n = 100; PCA: n = 50). Selection of initial pain control regimen showed no difference in average LOS (INT: 5.96 ± 4.19 days vs. PCA: 6.01 ± 3.47 days; P = .94) or 30-day readmission rates (INT: 21% vs. PCA: 16%; P = .52). Treatment failure was significantly higher in the INT group, occurring in 64% of patients vs. 14% in the PCA group (P < .0001). Pain scores were not significantly impacted by selection of pain regimen. Our study indicates that INT and PCA treatment modalities are both effective at controlling pain in VOC; however, more patients in the INT group were characterized as having a treatment failure. Based on our results, it is reasonable to initiate PCA as the primary pain treatment strategy in SCD patients presenting in VOC.
PMID: 30896312
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9. Curr Opin Hematol. 2019 Mar 18. doi: 10.1097/MOH.0000000000000491. [Epub ahead of print] Pain and sickle cell disease. Aich A1, Jones MK2, Gupta K2.. Abstract PURPOSE OF REVIEW: Pain is a major comorbidity of sickle cell disease (SCD). Opioids are the mainstay for pain treatment but remain suboptimal. We discuss mechanism-based treatable targets devoid of opioids to prevent and/or treat SCD pain. RECENT FINDINGS: Understanding the pathogenesis of pain is critical to develop targeted therapies. Nevertheless, acute and chronic pain can have independent and/or overlapping mechanisms. The origin of pain involves neurovascular and neuroimmune interactions from the periphery and/or central nervous system. Immunomodulatory components of acute and/or chronic sickle pain for targeting/preventing pain genesis include mast cell and microglial activation, neurogenic inflammation, and leukocyte-derived elastase. Vascular modulators include hypoxia/reperfusion injury, oxidative stress, hemolysis, and adhesion molecules. However, existent pain requires analgesics devoid of an inadvertent effect on sickle pathobiology. Recent analgesic targets include cannabinoid and nociceptin receptors and serotonergic spinothalamic pathway. Complementary approaches (e.g., acupuncture, hypnosis, perception-based therapies) have shown analgesic potential. Owing to heterogeneity in pain development, it remains challenging to combat SCD pain with any one therapy. SUMMARY: SCD pain involves neuroimmune and neurovascular interactions. Such interactions have pronociceptive impacts and impart therapy resistance. Elucidating molecular and cellular entities affecting neuronal interactions in sickle microenvironment may prevent SCD pain and/or provide improved analgesic approaches.
PMID: 30893088
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10. Curr Opin Pediatr. 2019 Mar 14. doi: 10.1097/MOP.0000000000000756. [Epub ahead of print] Asthma in children with sickle cell disease. Willen SM1, Rodeghier M2, DeBaun MR3. Abstract PURPOSE OF REVIEW: Asthma is common in children with sickle cell disease (SCD) and appears to be associated with increased morbidity. Providers caring for children with SCD have struggled with the question of whether asthma exists as a true comorbidity or whether certain aspects of the chronic inflammatory disease gives children with SCD an asthma-like phenotype. RECENT FINDINGS: Clinical signs and symptoms seen in children with asthma in the general population, such as wheezing, airway hyperresponsiveness, atopy, elevated leukotrienes, and abnormal lung function are seen in children with SCD both with and without a diagnosis of asthma. SUMMARY: Current evidence highlights that the presence of lung disease in children with SCD has significant implications irrespective of the underlying cause, including asthma. Further research should focus on well tolerated and effective interventions to prevent disease-related complications for children with pulmonary complications of SCD.
PMID: 30883397
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11. Transfus Apher Sci. 2019 Mar 13. pii: S1473-0502(19)30017-5. doi: 10.1016/j.transci.2019.03.004. [Epub ahead of print] Recommendations for the use of red blood cell exchange in sickle cell disease. Fort R1. Abstract Sickle cell disease (SCD) is a genetic disorder characterised by a single mutation of the beta globin gene, causing the production of an abnormal haemoglobin called sickle haemoglobin (HbS). In its deoxygenated form, HbS polymerises, causing major rheological disorders, which presents clinically as periodic vaso-occlusive crises, chronic haemolysis and chronic vascular dysfunction. Patients often resort to a background treatment, and transfusion remains the cornerstone in the management of the disease, significantly reducing morbidity and mortality. The aim of red blood cell exchange (RBCX) is to improve tissue oxygenation by increasing haemoglobin levels while lowering HbS levels. RBCX can be performed by manual or automated exchange, and each technique has its own set of advantages and disadvantages. This article will outline the transfusion indications for the main complications of SCD, as well as the most appropriate strategy to use. Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID: 30879904
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12. Br J Haematol. 2019 Mar 11. doi: 10.1111/bjh.15846. [Epub ahead of print] Risk of invasive pneumococcal disease in children with sickle cell disease in the era of conjugate vaccines: a systematic review of the literature. Oligbu G1, Fallaha M2, Pay L2, Ladhani S1,3. Abstract Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive pneumococcal diseases (IPD) in children, including those with sickle cell disease (SCD). A systematic review of the English literature published between 2000 and 2017 was undertaken to evaluate the serotype distribution, clinical presentation and outcomes of IPD in children with SCD in PCV programmes. We identified 475 potential studies and included 16 publications, involving 9438 children up to 22 years of age with SCD and 182 IPD episodes (prevalence, 1·9%. 95% confidence interval [CI], 1·7-2·2%). Septicaemia was the most prevalent clinical presentation (84/137; 61%) followed by lower respiratory tract infection (39/137; 29%) and meningitis (12/137, 9%). More than half the serotypes associated with IPD (88/148; 59·5%) were not included in the 13-valent PCV; of these, 54% (44/82) were due to serogroup 15. The crude case fatality rate was 11·5% (21/182 cases; 95% CI, 7·3-17·1%). Most cases of IPD in children with SCD were due to serotypes that are not included in any of the licensed PCVs. IPD in children with SCD remains associated with high morbidity and mortality, highlighting the importance of strict adherence to daily penicillin prophylaxis. Until a serotype-independent pneumococcal vaccine becomes available, higher-valent PCVs should include serogroup 15 to protect this highly vulnerable group of children. © 2019 British Society for Haematology and John Wiley & Sons Ltd.
PMID: 30859558
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13. Blood. 2019 Mar 11. pii: blood-2018-09-876318. doi: 10.1182/blood-2018-09-876318. [Epub ahead of print] Hydroxyurea reduces cerebral metabolic stress in patients with sickle cell anemia. Fields ME1, Guilliams KP2, Ragan D3, Binkley MM4, Mirro A5, Fellah S5, Hulbert ML1, Blinder M6, Eldeniz C7, Vo K7, Shimony JS7, Chen Y5, McKinstry RC7, An H7, Lee JM5, Ford AL8. Abstract Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs, and OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared to patients not receiving disease-modifying therapy, we prospectively obtained brain MRIs with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole brain CBF between the 3 cohorts (p = 0.148). However, whole brain OEF was significantly different (p < 0.001): participants without disease-modifying therapy had the highest OEF (42.9 [39.1-49.1]%), followed by HU treatment (40.7 [34.9-43.6]%), while CTT treatment had the lowest values (35.3 [32.2-38.9] %). Moreover, the percent of white matter at highest risk for ischemia, defined by OEF greater than 40 and 42.5%, was lower in the HU cohort compared to the untreated cohort (p = 0.025 and p = 0.034 respectively), but higher compared to the CTT cohort (p = 0.018 and p = 0.029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT. Copyright © 2019 American Society of Hematology.
PMID: 30858231
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14. Adv Hematol. 2019 Feb 3;2019:4397150. doi: 10.1155/2019/4397150. eCollection 2019. Double-Blind Clinical Trial of Arginine Supplementation in the Treatment of Adult Patients with Sickle Cell Anaemia. Eleutério RMN1, Nascimento FO2, Araújo TG1, Castro MF3, Filho TPA3, Filho PAM3, Eleutério J Jr4, Elias DBD3, Lemes RPG1,3. Abstract Background: Sickle cell anaemia (SCA) is the most prevalent monogenic disease in Brazil. In SCA, haemoglobin S (HbS) is formed, which modifies red blood cell morphology. Intravascular haemolysis occurs, in which free Hb and free radicals degrade nitric oxide (NO) and release arginase, which reduces arginine levels. Because arginine is a substrate for NO formation, this decrease leads to reduced NO (vasodilator) synthesis. SCA treatment uses hydroxyurea (HU) to maintain high foetal haemoglobin (HbF) levels and reduces HbS to avoid haemolytic episodes. Objective: To analyse the efficacy of L-arginine as an adjuvant in the treatment of SCA patients. Setting: The State Blood Centre of Ceará, Brazil. Methods: This was a randomized double-blind clinical study of adults with SCA with continuous use of HU at the State Blood Centre of Ceará. The clinical study enrolled 25 patients receiving HU + L-arginine (500 mg) and 25 patients receiving HU + placebo. The treatment was carried out over four months. Laboratory tests were performed to determine the levels of the following: (1) complete blood count; (2) nitrite + nitrate; (3) HbF; and (4) reticulocytes. The clinical experiments were performed by a haematologist. The main outcome measures were nitrite and pain. Results: Statistical analysis showed that the levels of NO were increased in the study group, and there was also a reduction in pain frequency using a pain frequency scale by day, week, and month. The levels of nitrite plus nitrate in the group receiving placebo plus HU did not change among the times evaluated (38.27 ± 17.27 mg/L, 39.49 ± 12.84 mg/L, 34.45 ± 11.25 mg/L, p >0.05), but in the patients who received supplementation with L-arginine plus HU, a significant increase in nitrite plus nitrate levels was observed between M0 and M4 (36.55 ± 20.23 mg/L versus 48.64 ± 20.63 mg/L, p =0.001) and M2 and M4 (35.71 ± 15.11 mg/L versus 48.64 ± 20.63 mg/L, p <0.001). It is important to note that the increase in nitrite plus nitrate levels occurred only in the fourth month of follow-up of patients in the treatment group, showing that at least 4 months of supplementation with L-arginine is necessary to show an increase in these metabolites in the serum. Conclusion: The use of L-arginine as a coadjuvant in the treatment of sickle cell anaemia may function as a potential tool for pain relief, consequently improving the life of patients. PMCID: PMC6378076 Free PMC Article
PMID: 30853991
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15. South Med J. 2019 Mar;112(3):190-197. doi: 10.14423/SMJ.0000000000000950. Lessons Learned from Building a Pediatric-to-Adult Sickle Cell Transition Program. Smith WR1, Sisler IY1, Johnson S1, Lipato TJ1, Newlin JS1, Owens ZS1, Morgan AM1, Treadwell MJ1, Polak K1. Abstract OBJECTIVE: More effective transitions and transfers of young people with sickle cell disease (SCD) into the adult healthcare setting is a focus of both primary care and specialty care medical organizations. Effective transition and transfer requires six core elements: establishing a policy, tracking progress, administering transition readiness assessments, planning for adult care, transferring to adult care, and integrating into an adult practice. We developed a program using these six core elements. The objective of our report was to assess the development and implementation of this program. METHODS: We used the six core elements to develop and implement a program at Virginia Commonwealth University for children and adolescents with SCD to transition to adult health care. RESULTS: We assessed individuals’ differences by age and grade, their independent living skills, their feelings about moving to adult care; tallied and analyzed several assessment scales; and assessed transfer success and patient retention. CONCLUSIONS: The principles and lessons we learned in developing and implementing this program over 5 years, accompanied by caring, flexible, and dedicated care team members, often can overcome even severe barriers to care transitions.
PMID: 30830235
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Sickle Cell Conferences and Events

 Sickle Cell Regional Conference: New & Emerging Therapies & Approaches to Management will be held on Saturday, May 18, 2019 in Mobile, AL. This one-day conference, presented by the University of South Alabama Comprehensive Sickle Cell Center, will be held at the USA Student Center. For more information on the conference visit: , Email or call 251-470-5893. Register online at: http//

Martin Center Sickle Cell Initiative will hold the 2019 Indiana Sickle Cell Conference on April 26, 2019 in Indianapolis, Indiana.  More information is available at  Speakers will be Dr. Marsha Treadwel (Keynote), Dr. Thomas Coates, Dr. Wally Smith and Dr. James Taylor.

Hemoglobinopathy Counselor Training Course will be held on April 17-18, 2019.  The two-day course, presented by the Cincinnati Comprehensive Sickle Cell Center, will be held at Cincinnati Children’s Hospital Medical Center.  The  course registration fee is $250. The deadline to register is April 1, 2019 and registration space is limited.  For more information, including a course brochure, please email:  Registration is also available online at

The Foundation for Sickle Cell Disease Research will be hosting its 13th Annual Symposium June 7-9, 2019 in Fort Lauderdale, FL. Registration is now open.  

Sickle Cell Disease Association of America’s 47th National Convention will be held October 9-12, 2019 in Baltimore, MD.

 5th Annual Sickle Cell Symposium: Saturday November 9th, 2019  At

The Speedway Club, 5555 Concord Parkway South Concord, NC 28027