First Successful  Gene Therapy in a Patient with Sickle Cell Disease

N Engl J Med 2017; 376:848-855 March 2, 2017

Sickle cell disease results from a homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like–globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease.

From Medscape News

Gene therapy that delivered an antisickling variant of hemoglobin in an autologous hematopoietic stem cell (HSC) transplant has ameliorated symptoms of severe sickle cell disease (SCD) in a 15-year-old boy, according to a report published in the March 2 issue of the New England Journal of Medicine.

SCD results from a point mutation at amino acid position 6 in the beta globin gene that causes polymerization of the protein and sickling of the erythrocytes that contain it, under low-oxygen conditions, obstructing microcirculation and damaging organs. Hemoglobin A (HbA) is the normal subunit; HbS is the one altered by the sickle cell mutation.

Hydroxyurea, which stimulates fetal hemoglobin production, is the only disease-modifying therapy for SCD; allogeneic hematopoietic stem cell transplant is curative. Fewer than 18% of people with severe SCD find transplant matches. For them, autologous transplant with a corrected beta globin gene — gene therapy — is a tantalizing chance at a possibly one-time treatment.

Jean-Antoine Ribeil, MD, PhD, from the Reference Centre for Sickle Cell Disease, Necker Children’s Hospital, Paris, France, and colleagues introduced a lentiviral vector bearing an antisickling variant of HbA into a boy when he was 13 years old. The patient “had complete clinical remission with correction of hemolysis and biologic hallmarks of the disease,” they write.

The boy had a severe presentation, including vaso-occlusive crises, acute chest syndrome, and bilateral hip osteonecrosis, and had had his spleen and gallbladder removed. Hydroxyurea treatment between ages 2 and 9 years was ineffective, and he had also received prophylactic red cell transfusions and iron chelation. The patient enrolled in the clinical trial in May 2014 and received the LentiGlobin (bluebird bio, Inc) gene therapy in October 2014.

The alteration in the beta globin gene creates an antisickling effect similar to that of gamma globin, the subunit of fetal hemoglobin. The altered hemoglobin dampens polymerization of HbS and is also distinguishable from other globin chains using reverse-phase high-performance liquid chromatography. The boy’s bone marrow was conditioned with busulfan, which provides room for repopulation, and was enriched for CD34+ stem cells.

Red cell transfusions continued until the transplanted cells began to produce altered Hb, ceasing on day 88. By the ninth month posttransplant, levels of HbA were 5.5 g/dL (46%), increasing to 5.7 g/dL (48%) by the fifteenth month. By the 18-month mark, which the researchers reported at the American Hematology Society meeting in December 2016, HbA level had risen to 6.6 g/dL (53%). At the same time, levels of HbS fell.

At 12 months, the proportion of sickled cells in the patient and his oxygen saturation levels were similar to those of his mother, a heterozygote. Proportions of all blood cell types had normalized.

Adverse events were minimal, resolved quickly, and were entirely caused by the busulfan conditioning. Bilirubin, lactate dehydrogenase, and reticulocyte count all decreased to normal levels.

The researchers monitored viral integration sites and confirmed a polyclonal response to the replacement HSCs — measures taken to ensure that the viruses did not integrate into proto-oncogenes. Some of the investigators were part of the team linking retroviral vectors to insertional oncogenesis to treat severe combined immunodeficiency type X1. Lentivirus has not been associated with that risk.

The only limitation to the case report is that transfusion before the procedure interfered with conducting certain before and after comparisons. A second research group testing the same gene therapy reported findings at the American Hematology Society meeting. Their seven patients have shown more modest improvement than the French cohort, but have not been followed as long.

“HbAT87Q expression appears to be sufficient to suppress hemolysis, resulting in stable hemoglobin concentrations of 11 to 12 g per deciliter and major improvement in all measurable sickle cell disease–specific biologic markers and blocking sickle cell disease–related clinical events,” the researchers conclude.

The benefits of the approach include lowered risk for rejection compared with allogeneic transplant, no need for a donor, and “one treatment that could result in a permanent, curative outcome,” Steven J. Gray, PhD, from the Gene Therapy Center at the University of North Carolina, Chapel Hill, told Medscape Medical News. Dr Gray designed the viral vector for the giant axonal neuropathy gene therapy clinical trial and others.

“This is one of the classic genetic diseases everyone learns about in freshman biology. As someone who works in the area of gene therapy every day, the realistic prospect of curing sickle cell disease with gene therapy is simply astonishing. This provides hope that the next generation of students will read about the devastation of this disease in history books only,” Dr Gray added.


Articles in the medical literature


  1. J Natl Med Assoc. 2017 Spring;109(1):36-43. doi: 10.1016/j.jnma.2016.10.003. Epub 2016 Nov 8.

Vitamin D Deficiency in Adult Sickle Cell Patients.

Boettger PC1, Knupp CL2, Liles DK2, Walker K2.


Vitamin D levels in adult black Americans with sickle cell disease (SCD) are comparatively lower than those found in the general population of black Americans. The objectives of this study were to examine the prevalence of Vitamin D deficiency (VDD) in adults with various subtypes of sickle cell disease and identify risk factors for vitamin D deficiency.


In a retrospective study serum Vitamin D25(OH)D and/or VitaminD1,25(OH)2D levels were obtained in 120 subjects with sickle cell disease. Baseline studies also included LFTs, total protein, albumin, total bilirubin, and creatinine levels. In a portion of subjects that were treated with oral ergocalciferol vitamin D levels and chemistries were obtained within 6 months of treatment. Data was statistically analyzed with Welch two sample t-tests and individual simple linear regressions (including logarithmic values) for each variable.


Vitamin D25(OH)D levels were found to be significantly lower in a group of subjects with Hgb SS disease, than in a group with other subtypes of sickle cell disease. In both groups combined, significant (p = 0.05) and clinically suggestive negative correlations with Vitamin D25(OH)D were seen for total bilirubin and total protein, respectively. When total bilirubin and total protein levels were compared between the Hgb SS and HgbS/other groups, t-test revealed these levels were significantly higher in the Hgb SS group levels at p < 0.001 and p = 0.005, respectively.


Low total Vitamin D25(OH)D levels in adults with sickle cell disease may be a reflection of chronic inflammation and overall disease severity.

Copyright © 2016 National Medical Association. Published by Elsevier Inc. All rights reserved.

PMID: 28259214 [PubMed – in process]

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Sickle cell disease in Saudi Arabia: A challenge or not.

Alotaibi MM1.

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  1. J Community Genet. 2017 Mar 1. doi: 10.1007/s12687-017-0294-8. [Epub ahead of print]

Voluntary premarital screening to prevent sickle cell disease in Jamaica: does it work?

Serjeant GR1,2, Serjeant BE3,4, Mason KP3,4, Gibson F3, Gardner R3, Warren L3, Jonker M5,6.


To determine whether identifying haemoglobin genotype, and providing education and counselling to senior school students will influence their choice of partner and reduce the frequency of births with sickle cell disease. The Manchester Project provided free voluntary blood tests to determine haemoglobin genotype to the fifth and sixth forms (grades 11-13), median age of 16.7 years, of all 15 secondary schools in the parish of Manchester in south central Jamaica. A total of 16,636 students complied, and counselling was offered to carriers of abnormal genes over 6 years (2008-2013). The genotypes of their offspring were determined by newborn screening of 66,892 deliveries in 12 regional hospitals over 8 years (2008-2015). The study focused on the genotypes of live deliveries to female students with the four most common haemoglobin genotypes: 7905 with an AA genotype, 898 with the sickle cell trait, 326 with the HbC trait and 78 with the beta thalassaemia trait. A total of 2442 live deliveries were identified by the end of 2015 in mothers screened at school. Eleven babies had clinically significant genotypes, and the prevalence of SS and SC disease did not differ from that predicted by random mating. First pregnancy was not delayed in AS or AC mothers. There was no evidence that knowledge of maternal haemoglobin genotype influenced choice of partner. On an interview, mothers of affected babies correctly recalled their genotype, but either did not discuss this with their partners or the latter refused to be tested. Subjects delaying child bearing for tertiary education would be largely excluded from the present study of first pregnancies and may make greater use of this information. Future options are a greater role for prenatal diagnosis.

PMID: 28251585 [PubMed – as supplied by publisher]

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  1. N Engl J Med. 2017 Mar 2;376(9):848-855. doi: 10.1056/NEJMoa1609677.

Gene Therapy in a Patient with Sickle Cell Disease.

Ribeil JA1, Hacein-Bey-Abina S1, Payen E1, Magnani A1, Semeraro M1, Magrin E1, Caccavelli L1, Neven B1, Bourget P1, El Nemer W1, Bartolucci P1, Weber L1, Puy H1, Meritet JF1, Grevent D1, Beuzard Y1, Chrétien S1, Lefebvre T1, Ross RW1, Negre O1, Veres G1, Sandler L1, Soni S1, de Montalembert M1, Blanche S1, Leboulch P1, Cavazzana M1.


Sickle cell disease results from a homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector-mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like-globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 number, NCT02151526 .).

PMID: 28249145 [PubMed – in process]

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  1. J Clin Invest. 2017 Mar 1;127(3):750-760. doi: 10.1172/JCI89741. Epub 2017 Mar 1.

Intravascular hemolysis and the pathophysiology of sickle cell disease.

Kato GJ, Steinberg MH, Gladwin MT.


Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. Decompartmentalized hemoglobin, arginase 1, asymmetric dimethylarginine, and adenine nucleotides are all products of hemolysis that promote vasomotor dysfunction, proliferative vasculopathy, and a multitude of clinical complications of pulmonary and systemic vasculopathy, including pulmonary hypertension, leg ulcers, priapism, chronic kidney disease, and large-artery ischemic stroke. Nitric oxide (NO) is inactivated by cell-free hemoglobin in a dioxygenation reaction that also oxidizes hemoglobin to methemoglobin, a non-oxygen-binding form of hemoglobin that readily loses heme. Circulating hemoglobin and heme represent erythrocytic danger-associated molecular pattern (eDAMP) molecules, which activate the innate immune system and endothelium to an inflammatory, proadhesive state that promotes sickle vaso-occlusion and acute lung injury in murine models of sickle cell disease. Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. These pathological responses promote regional vasoconstriction and subsequent blood vessel remodeling. Thus, intravascular hemolysis represents an intrinsic mechanism for human vascular disease that manifests clinical complications in sickle cell disease and other chronic hereditary or acquired hemolytic anemias.

PMID: 28248201 [PubMed – in process]

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  1. Pharmacogenomics. 2017 Mar;18(4):321-325. doi: 10.2217/pgs-2016-0007. Epub 2017 Feb 17.

Is there a role for pharmacogenetics in the treatment of sickle cell disease?

Wonkam A1,2.

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  1. Arch Pathol Lab Med. 2017 Mar;141(3):329-340. doi: 10.5858/arpa.2016-0277-SA.

Genotyping Applications for Transplantation and Transfusion Management: The Emory Experience.

Fasano RM, Sullivan HC, Bray RA, Gebel HM, Meyer EK, Winkler AM, Josephson CD, Stowell SR, Sandy Duncan A, Roback JD1.


Current genotyping methodologies for transplantation and transfusion management employ multiplex systems that allow for simultaneous detection of multiple HLA antigens, human platelet antigens, and red blood cell (RBC) antigens. The development of high-resolution, molecular HLA typing has led to improved outcomes in unrelated hematopoietic stem cell transplants by better identifying compatible alleles of the HLA-A, B, C, DRB1, and DQB1 antigens. In solid organ transplantation, the combination of high-resolution HLA typing with solid-phase antibody identification has proven of value for highly sensitized patients and has significantly reduced incompatible crossmatches at the time of organ allocation. This database-driven, combined HLA antigen/antibody testing has enabled routine implementation of “virtual crossmatching” and may even obviate the need for physical crossmatching. In addition, DNA-based testing for RBC antigens provides an alternative typing method that mitigates many of the limitations of hemagglutination-based phenotyping. Although RBC genotyping has utility in various transfusion settings, it has arguably been most useful for minimizing alloimmunization in the management of transfusion-dependent patients with sickle cell disease or thalassemia. The availability of high-throughput RBC genotyping for both individuals and large populations of donors, along with coordinated informatics systems to compare patients’ antigen profiles with available antigen-negative and/or rare blood-typed donors, holds promise for improving the efficiency, reliability, and extent of RBC matching for this population.

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  1. J Pediatr Hematol Oncol. 2017 Feb 17. doi: 10.1097/MPH.0000000000000787. [Epub ahead of print]

Body Mass Index and the Association With Vaso-occlusive Crises in Pediatric Sickle Cell Disease.

Zivot A1, Apollonsky N, Gracely E, Raybagkar D.



Children with sickle cell disease (SCD) historically have been underweight and have poor overall growth. Recent studies have demonstrated a trend toward obesity in pediatric SCD populations.


Through retrospective chart review of patients with SCD followed at our center, we collected patient’s data, including body mass index (BMI), weight percentiles, sickle cell genotype, baseline hemoglobin, medical and psychiatric comorbidities, 25-hydroxy vitamin D level, treatment with hydroxyurea, and chronic transfusions. We identified hospitalizations to St. Christopher’s Hospital for vaso-occlusive crisis (VOC) and duration of hospitalization and intravenous opioid use were recorded. Student t test, Mann-Whitney U test, and analysis of variance were used to examine associations between variables and frequency and duration of hospitalizations for VOC.


Among 328 patients with SCD, overweight and obese children constituted 19% of hospitalized and nonhospitalized patients. BMI status did not influence frequency (P=0.90) or duration of hospitalization (P=0.65) for VOC. Obesity was more associated with HbSC than HbSS (P=0.025) genotype.


Our study did not demonstrate an association between extremes of BMI of patients and hospitalization for VOC. Considering current trend toward obesity, further prospective and interventional research are required to define the effects of extremes of BMI on pain crises in SCD.

PMID: 28221266 [PubMed – as supplied by publisher]

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  1. West J Emerg Med. 2017 Feb;18(2):251-252. doi: 10.5811/westjem.2016.12.33224. Epub 2017 Jan 30.

Management of Sickle Cell Disease Super Utilizers.

Johnson GA1.

PMCID: PMC5305133 Free PMC Article


PMID: 28210360 [PubMed – in process]

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  1. J Pain Symptom Manage. 2017 Feb 9. pii: S0885-3924(17)30050-7. doi: 10.1016/j.jpainsymman.2016.12.351. [Epub ahead of print]

A Randomized Trial of Yoga for Children Hospitalized with Sickle Cell Vaso-Occlusive Crisis.

Moody K1, Abrahams B2, Baker R3, Santizo R2, Manwani D2, Carullo V2, Eugenio D2, Carroll A3.



Sickle cell disease (SCD) vaso-occlusive crisis (VOC) remains an important cause of acute pain in pediatrics and the most common SCD complication. Pain management recommendations in SCD include nonpharmacological interventions. Yoga is one nonpharmacological intervention that has been shown to reduce pain in some populations, however, evidence is lacking in children with VOC.


The primary objective of this study was to compare the effect of yoga versus an attention control on pain in children with VOC. The secondary objectives were to compare the effect of yoga versus an attention control on anxiety, length of stay (LOS) and opioid use in this population.


Patients were eligible if they had a diagnosis of SCD, were 5-21 years old, were hospitalized for uncomplicated VOC, and had an admission pain score > 7. Subjects were stratified based on disease severity and randomized to the yoga or control group.


Eighty-three percent of patients approached (N=73) enrolled on study. There were no significant differences in baseline clinical or demographic factors between groups. Compared with the control group, children randomized to yoga had a significantly greater reduction in mean pain score after 1 yoga session (-0.6 ±0.96 v. 0.0 ±1.37; p=0.029). There were no significant differences in anxiety, LOS, or opioid use between the two groups.


This study provides evidence that yoga is an acceptable, feasible, and helpful intervention for hospitalized children with VOC. Future research should further examine yoga for children with SCD pain in the inpatient and outpatient settings.

Copyright © 2017. Published by Elsevier Inc.

PMID: 28192225 [PubMed – as supplied by publisher]

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  1. Med Clin North Am. 2017 Mar;101(2):375-393. doi: 10.1016/j.mcna.2016.09.009. Epub 2016 Dec 14.

Sickle Cell Disease: A Brief Update.

Azar S1, Wong TE2.


Sickle cell disease (SCD) is an inherited monogenic disease characterized by misshapen red blood cells that causes vaso-occlusive disease, vasculopathy, and systemic inflammation. Approximately 300,000 infants are born per year with SCD globally. Acute, chronic, and acute-on-chronic complications contribute to end-organ damage and adversely affect quantity and quality of life. Hematopoietic stem cell transplantation is the only cure available today, but is not feasible for the vast majority of people suffering from SCD. Fortunately, new therapies are in late clinical trials and more are in the pipeline, offering hope for this unfortunate disease, which has increasing global burden.

Copyright © 2016 Elsevier Inc. All rights reserved.

PMID: 28189177 [PubMed – in process]

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  1. Blood Cells Mol Dis. 2017 Feb 2. pii: S1079-9796(16)30138-3. doi: 10.1016/j.bcmd.2017.01.014. [Epub ahead of print]

A systematic review of the literature for severity predictors in children with sickle cell anemia.

Meier ER1, Fasano RM2, Levett PR3.


All patients with HbSS (SCA) share the same genetic mutation but the clinical phenotype is variable and difficult to predict early in life. A reliable severity predictor would be invaluable toward directing therapeutic decisions in those patients at highest risk of SCA complications. A search of PubMed, Cochrane Clinical Trials Register, and Scopus was performed to determine which SCA severity predictors have been validated in pediatric patients. The full text of 94 of the 590 references identified was reviewed based on the title/abstract. Fifty-four articles were included in the analysis. Alpha globin gene number was the most commonly studied severity predictor, followed by fetal hemoglobin (HbF) and reticulocyte count. Alpha thalassemia trait was protective against overt stroke and abnormal transcranial Doppler (TCD) in all but one study, but not frequency of painful crisis or silent cerebral infarct. Two thirds of the HbF studies reported beneficial effects with increasing HbF levels; however, increased HbF levels were not associated with lower hospitalization or stroke rates in others. The ability to predict SCA complications was mixed for all variables, except TCD and absolute reticulocyte count. More reliable predictors are urgently needed to guide therapeutic decisions in children with SCA.

Copyright © 2017 Elsevier Inc. All rights reserved.

PMID: 28185829 [PubMed – as supplied by publisher]

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  1. Med Educ Online. 2016 Jan;21(1):33616. doi: 10.3402/meo.v21.33616.

Translating sickle cell guidelines into practice for primary care providers with Project ECHO.

Shook LM1, Farrell CB1, Kalinyak KA1, Nelson SC2, Hardesty BM3, Rampersad AG3, Saving KL4, Whitten-Shurney WJ5, Panepinto JA6, Ware RE1, Crosby LE7.


Background Approximately 100,000 persons with sickle cell disease (SCD) live in the United States, including 15,000 in the Midwest. Unfortunately, many patients experience poor health outcomes due to limited access to primary care providers (PCPs) who are prepared to deliver evidence-based SCD care. Sickle Treatment and Outcomes Research in the Midwest (STORM) is a regional network established to improve care and outcomes for individuals with SCD living in Indiana, Illinois, Michigan, Minnesota, Ohio, and Wisconsin. Methods STORM investigators hypothesized that Project ECHO® methodology could be replicated to create a low-cost, high-impact intervention to train PCPs in evidence-based care for pediatric and young adult patients with SCD in the Midwest, called STORM TeleECHO. This approach utilizes video technology for monthly telementoring clinics consisting of didactic and case-based presentations focused on the National Heart, Lung and Blood Institute (NHLBI) evidence-based guidelines for SCD. Results Network leads in each of the STORM states assisted with developing the curriculum and are recruiting providers for monthly clinics. To assess STORM TeleECHO feasibility and acceptability, monthly attendance and satisfaction data are collected. Changes in self-reported knowledge, comfort, and practice patterns will be compared with pre-participation, and 6 and 12 months after participation. Conclusions STORM TeleECHO has the potential to increase implementation of the NHLBI evidence-based guidelines, especially increased use of hydroxyurea, resulting in improvements in the quality of care and outcomes for children and young adults with SCD. This model could be replicated in other pediatric chronic illness conditions to improve PCP knowledge and confidence in delivering evidence-based care.

PMID: 28165949 [PubMed – in process]

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Sickle Cell Conferences and Events


Foundation for Sickle Cell Disease Research Annual meeting

April 28 -30 2017 Ft Lauderdale FL

Hemoglobinopathy Counselor Training Course will be held on April 6-7, 2016.  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 $200. The deadline to register is March 24, 2017 and registration is limited.  For more information, including a course brochure, please email:  Registration is also available online at