Amplicon-sequencing of BCL11a-edited stem cells used to treat beta thalassemia and sickle cell disease suffices to demonstrate that CRISPR is a chromosome shredder

2019 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Clinical Trials ◽  
Target Gene ◽  
Fetal Hemoglobin ◽  
Amplicon Sequencing ◽  
Beta Thalassemia ◽  
Conservative Estimate ◽  
Cell Disease ◽  
High Confidence ◽  
Gene Space ◽  
Cell Study

The quanta of ’genome vandalism’ CRISPR does is easily observed by amplicon sequencing of the target gene. The algorithm chooses reads that match the targeted gene GENE, but also another gene (OFFGENE) - meaning there has been a translocation/integration. This translocation/integration is possible if and only if OFFGENE has also been edited - an off-target. Larger the number of reads with GENE-OFFGENE, larger the confidence. For example, the stem-cell study, which edits BCL11a to increase fetal hemoglobin, has 111 BCL11a-RNA45SN5 reads [1]. Analysis of the edit location in RNA45SN5 shows 8 mismatches with the gRNA, which falls within the permissible limits [2]. There are 20 such genes which have integrated with the BCL11a gene with high confidence. This is a very conservative estimate for two reasons. First, amplicon-sequencing only looks at GENE. If two OFFGENE’s were integrating, the data would not show that. Secondly, I have only looked the gene space - so only 2% of the genome. Since we find 20 genes integrating with BCL11a after such constraints, it is fair to assume that CRISPR is literally shredding the chromosome - a possible reason for significant fatalities in clinical trials [3].

Decitabine Improves Clinical Outcomes in Severely Ill Sickle Cell Disease Patients Who Have Exhausted Standard of Care Options.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3792-3792
Author(s):  
Yogenthiran Saunthararajah ◽  
Robert Molokie ◽  
Seema Sidhwani ◽  
Santosh Saraf ◽  
Stephen Vara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Clinical Trials ◽  
Low Dose ◽  
Performance Status ◽  
Fetal Hemoglobin ◽  
Standard Of Care ◽  
Cell Disease ◽  
Off Label ◽  
Clinically Significant

Abstract Interventions such as immunization, penicillin prophylaxis, hydroxyurea and transfusion have extended life in patients with sickle cell disease (SCD). Nonetheless, these interventions are limited by toxicity or effectiveness; continued substantial morbidity and mortality in SCD indicates the need for better disease modification. In previous phase I/II clinical trials, 13 of 13 patients treated with the DNA hypomethylating agent decitabine responded with clinically significant fetal hemoglobin and total hemoglobin elevation and improvement in surrogate clinical end-points. However, in these early studies, no clinical end-points were measured and further studies have been delayed by funding issues. We describe an off-label experience in four patients with severe SCD that suggests remarkable clinical effectiveness in patients who have exhausted standard of care and are severely ill; tolerability even in the severely ill; a mechanism of action based on increased reticulocytosis in addition to increased fetal hemoglobin. All four patients had multiple alloantibodies and red-cell auto-antibodies that limited availability and increased risks of transfusion, and had previously been treated with hydroxyurea with continued clinical deterioration. Three of the four patients had relative reticulocytopenia (absolute reticulocyte count <250x109/L and hemoglobin <9g/dl) and were receiving erythropoietin or darbopoietin for more than 8 weeks with continued progressive anemia and progressive congestive heart failure. All four patients were ECOG performance status 3 and ineligible for available clinical trials. Based on the clinical trial experience conducted at our institution, decitabine therapy at 0.1–0.2 mg/kg 1–2X/week was initiated in these patients not for research purposes but with the intent to produce direct clinical benefit. The limited clinical data and potential for unanticipated toxicity was discussed in full with each patient and family members. IRB approval was obtained for a retrospective chart review. No decitabine related adverse events occurred. All patients demonstrated >2g/dl increases in hemoglobin levels with an associated improvement in clinical status - decrease in pain, improvement in performance status, improvement in congestive heart failure symptoms/signs. Upward trends in the platelet and reticulocyte counts concurrent with downward trends in the neutrophil counts were consistent with previously observed effects of low dose decitabine or the related compound 5-azacytidine. Clinically significant neutropenia was avoided by dose reductions that did not reverse the improved hemoglobin levels. The differentiation altering effects of low dose decitabine relieve SCD anemia by decreasing hemolysis (through elevated HbF) and increasing reticulocytosis. Previous clinical trials, and this off-label experience, suggest that decitabine holds remarkable promise as a disease modifying agent for SCD and β-thalassemia. Further clinical trials to confirm this impression should be supported.

Functional Characterisation of a MYB-HBS1L Intergenic Region Controlling Fetal Hemoglobin Levels in Adults

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 488-488
Author(s):  
Karin E Wahlberg ◽  
Jie Jiang ◽  
Helen Rooks ◽  
Steve Best ◽  
Swee Lay Thein
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Intergenic Region ◽  
Regulatory Region ◽  
Fetal Hemoglobin ◽  
Regulatory Elements ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Hypersensitive Sites ◽  
Chip Chip

Abstract A major ameliorating factor in sickle cell disease and beta-thalassemia is the inherent ability to produce fetal hemoglobin (HbF, a2g2), a highly heritable trait. We have previously mapped a major quantitative trait locus (QTL) controlling HbF levels to an array of single nucleotide polymorphisms (SNPs) within a 79 kb block between the gene for HBS1L (a G-protein/elongation factor) and the MYB proto-oncogene in Northern European Caucasians. These variants in chromosome 6q23.3, are referred to as HBS1L-MYB intergenic polymorphism (HMIP) and exist in three linkage disequilibrium (LD) blocks, HMIP-1, -2 and -3, of which HMIP-2 shows the strongest association. Association of HMIP with HbF has recently been replicated in two independent cohorts of patients with sickle cell disease, African-American and Brazilian, as well as in a cohort of Chinese patients with beta-thalassemia. Physiologically, MYB and HBS1L expression was simultaneously down-regulated in individuals with high HbF while over-expression of MYB inhibits gamma-globin expression. We also showed that HMIP influences erythrocyte, platelet and monocyte counts in humans. We hypothesised that the genetic variants in the MYB-HBS1L intergenic region are situated in a regulatory region and affect HbF levels by altering the expression of MYB and/or HBS1L. Initial DNase I hypersensitivity analysis of the HMIP-2 region in K562 cells identified a number of hypersensitive sites which encouraged further functional analysis of the region. To study activity and to map potential regulatory elements in the entire MYB-HBS1L region we used chromatin immunopreciptation on microarray (ChIP–chip) of acetylated histones H3 and 4, RNA polymerase II and GATA-1. ChIP was performed on chromatin from primary human erythroid precursor cells and enrichment for specific sequences was evaluated using a high resolution Nimblegen microarray covering a large part of chromosome 6q. Our ChIP-chip data show high levels of histone acetylation in the MYB-HBS1L intergenic region with a concentration in the HMIP-2 block, indicating that the region is transcriptionally active in erythroid precursors. Moreover, a number of potential cis-regulatory elements were identified in the same region as strong GATA-1 signals in coincidence with DNase I hypersensitive sites. These results suggest a regulatory region in the MYB-HBS1L intergenic region that could be important in erythroid development by controlling expression in the MYB locus.

Induction of Human Fetal Hemoglobin Expression by Selective Inhibitors of Histone Deacetylase 1 and 2 (HDAC1/2)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3259-3259
Author(s):  
Jeffrey R Shearstone ◽  
John H van Duzer ◽  
James E Bradner ◽  
Ralph Mazitschek ◽  
Simon S Jones ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Dna Methyltransferase ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Selective Inhibitors ◽  
Genetic Ablation ◽  
Histone Deacetylase 1 ◽  
Hbf Induction ◽  
Equity Ownership

Abstract Abstract 3259 Introduction: Fetal hemoglobin (HbF) induction is an established therapeutic strategy in sickle cell disease (SCD), and could also be effective in treating beta-thalassemia (bT). The only drug with proven efficacy in SCD is hydroxyurea, which is cytotoxic, poorly tolerated, and only reduces the frequency and severity of SCD crises in a subset of patients. For bT there are no approved drug treatments and, for the most severe forms of bT, patients require repeated blood transfusions for life and chelation therapy to reduce iron overload. Fetal (γ) globin expression is silenced in adults partly through the action of a complex containing BCL11A and HDAC1/2. Genetic ablation and chemical inhibition of HDAC1 or HDAC2, but not HDAC3, resulted in the induction of γ-globin synthesis in adult bone marrow derived CD34+ erythroid cells (Bradner, Proc Natl Acad Sci 2010). While a variety of non-specific HDAC inhibitors have been used successfully to induce HbF, further clinical development has been limited by their variable efficacy and concerns over off-target side-effects observed in small clinical trials, potentially due to inhibition of HDAC3. Therefore, development of selective and potent HDAC1/2 inhibitors leading to HbF induction represents a refined and targeted therapeutic approach for the treatment of SCD and bT. Results: Recently, selective inhibitors for HDAC1 and 2 have been described for compounds containing a benzamide zinc chelating group (Witter, Bioorg Med Chem Lett 2008). Acetylon Pharmaceuticals has generated a library of structurally distinct compounds containing a modified benzamide biasing element. We have screened these molecules in an HDAC biochemical assay platform and found IC50 values for HDAC1 and 2 ranging from 5 to 10 nM and 10 to 30 nM, respectively, with approximately 10- to 100-fold selectivity over inhibition of HDAC3. These compounds had good oral bioavailability in rat, with exposure (AUC) exceeding 5000 hr*ng/mL following an oral dose of 5 mg/kg. Furthermore, half-life was found to range between 4 to 8 hours. In cultured human CD34+ bone marrow cells undergoing erythroid differentiation, these compounds induced a dose dependent increase in fetal hemoglobin expression, with a 5-fold induction observed at 1 μM. The γ-globin induction we observe is comparable to MS-275, a non-selective HDAC1/2/3 inhibitor, and decitabine, a DNA methyltransferase inhibitor which has been in clinical trials to induce HbF in SCD. The absolute levels of adult β-globin remained unchanged. These results were confirmed using flow cytometry, where a 2- to 4-fold increase in the number of cells expressing HbF protein was observed. Conclusion: These results suggest that inhibition of HDAC1 and 2 is sufficient to induce fetal globin expression. Our selective HDAC1/2 inhibitors have highly favorable oral pharmacokinetic profiles suitable for further development towards the treatment of SCD and bT. Disclosures: Shearstone: Acetylon Pharmaceuticals, Inc.: Employment. van Duzer:Acetylon Pharmaceuticals, Inc.: Employment. Bradner:Acetylon Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mazitschek:Acetylon Pharmaceuticals, Inc. : Consultancy, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc.: Employment. Jarpe:Acetylon Pharmaceuticals, Inc.: Employment.

Additive Effect of Butyrate and Hemin on Fetal Hemoglobin Induction in Erythroid Cells from Sickle Cell Disease and Beta-Thalassemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1224-1224
Author(s):  
Hassana Fathallah ◽  
Ali Taher ◽  
Ali Bazarbachi ◽  
George F. Atweh
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Histone Deacetylases ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Erythroid Cells ◽  
Cell Disease ◽  
Globin Mrna ◽  
In Erythroid Cells

Abstract High levels of fetal hemoglobin (HbF) are known to ameliorate the pathophysiology of β-globin disorders. The objective of this study is twofold: the first is to evaluate the efficacy of hemin as an inducer of HbF in erythroid cells from patients with sickle cell disease (SCD) and β-thalassemia (β-thal); the second is to determine if the combination of butyrate and hemin can induce higher levels of expression of HbF than either agent alone. BFU-E derived cells from the peripheral blood of two patients with homozygous SCD, three patients with β-thal, one patient with sickle β-thalassemia (S/β-thal) and one normal individual (AA) were cultured in the absence (control) or presence of butyrate (B), hemin (H) or butyrate and hemin (B+H). As expected, the levels of γ-globin mRNA [expressed as % γ/(β+γ)] increased upon butyrate exposure in progenitor-derived erythroid cells from SS and S/β-thal patients, and to a lesser extent in patients with β-thal (P = 0.01). In contrast, butyrate did not increase γ-globin expression in BFU-E derived colonies from the AA individual. Moreover, hemin exposure increased the γ/(β+γ) ratio in all subjects (P = 0.02). These findings confirm that hemin can be an effective HbF inducing agent in SCD and β-thal. Although the mechanism of induction of HbF by hemin is not known, unlike butyrate, hemin is clearly not a direct inhibitor of histone deacetylases and is likely to induce HbF by a different mechanism of action. Thus, we investigated the effect of the combination of hemin and butyrate on γ-globin gene expression. Interestingly, the combination of butyrate and hemin resulted in additive increases in the γ/(β+γ) ratios in all patients compared to butyrate alone (P = 0.03) or hemin alone (P = 0.01) (Table I). Just as importantly, exposure to both drugs resulted in a decrease in the α/(β+γ) mRNA imbalance in β-thal, which is the predominant pathophysiological feature of this disorder. In conclusion, combination therapy consisting of butyrate and hemin, which are two agents with different mechanisms of action and different toxicity profiles, may provide a more effective way of inducing HbF in patients with SCD and β-thal. Table I mRNA SCD β-Thal S/β-Thal AA n 2 3 1 1 %γ/(β+γ) Control 36 42 26 7.1 B 45 50 41 6.9 H 55 55 52 15 B+H 60 61 59 13 α/(β+γ) Control 3.1 8.9 1.8 1.9 B 2.0 7.7 2.9 1.7 H 3.0 7.5 1.7 1.0 B+H 2.9 6.4 2.2 1.3

Fetal Hemoglobin Expression Is Differentially Affected by Inhibition of the Proposed Dred Complex Constituents, LSD1 and DNMT1

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3263-3263 ◽  
Author(s):  
Tara L Arvedson ◽  
Lynn Tran ◽  
Sandra L Ross ◽  
Sean Yoder ◽  
Alexandra Hertz ◽  
...  
Keyword(s):  
Fetal Hemoglobin ◽  
Erythroid Differentiation ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Hematopoietic Progenitor ◽  
Gamma Globin ◽  
Hbf Induction ◽  
Effect Of Treatment ◽  
Globin Promoter

Abstract Abstract 3263 Introduction Sickle cell disease and beta thalassemia are disorders caused by mutations in adult hemoglobin (HbA) or defects in HbA expression. A potential therapeutic solution is reactivation of fetal hemoglobin (HbF) expression. Although HbF, comprising two alpha and two gamma globin chains, is the primary form of hemoglobin expressed in utero, gamma globin expression is silenced in adults. One proposed mechanism of gamma globin silencing involves binding of the direct repeat erythroid definitive (DRED) repressor complex to sequences in the gamma globin promoter. The DRED complex is reported to include the orphan nuclear hormone receptors TR2 and TR4, lysine specific demethylase (LSD1) and DNA methyltransferase (DNMT1). As both LSD1 and DNMT1 are epigenetic modifiers, gamma globin repression is proposed to be mediated by LSD1- and DNMT1-induced epigenetic changes. To investigate the role of DNMT1 and LSD1 in HbF silencing, HbF expression was evaluated in an erythroid differentiation model where hematopoietic progenitor cells were treated with either DNMT1 or LSD1 small molecule inhibitors or siRNA. Methods Human hematopoietic progenitor cells from healthy donors were induced to become erythroid using a two step protocol including erythropoietin, SCF, IL-3 and hydrocortisone for days 1–7 and erythropoietin and SCF for days 8–14. Cultures were treated with a range of concentrations of either tranylcypromine or S2101 (LSD1 inhibitors) or 5-azacytidine (DNMT1 inhibitor) and compared to HbF-inducing, positive control small molecules pomalidomide and lenalidomide. Cultures were also treated with LSD1 siRNAs and compared to controls. The effect of treatment on gamma, beta and alpha globin transcription was determined by qRT-PCR. The effect of treatment on HbA and HbF levels was determined by ELISA, HPLC, flow cytometry and imaging. Differentiation was characterized by morphology and flow-based detection of CD34 and glycophorin. Effects on viability were characterized by ViCell and flow cytometry. Results Treatment with a concentration range of 5-azacytidine increased the rate of red blood cell differentiation as measured by daily changes in CD34 and glycophorin and hemoglobinization. Quantitative ELISA demonstrated that HbF expression increased two-fold. In contrast, LSD1 inhibition reduced both the rate of proliferation and differentiation of erythroid progenitors. Consistent with impaired differentiation, both beta globin transcription and HbA expression were reduced by up to 84% (qRT-PCR) and 65% (quantitative ELISA), respectively. No increase in gamma globin transcription or HbF expression was observed in response to LSD1 inhibition. Control cultures differentiated as expected: after 14 days of treatment the majority of vehicle-, lenalidomide- or pomalidomide-treated cells were glycophorin-positive and enucleation was readily apparent. Both lenalidomide and pomalidomide treatment induced a two-fold increase in HbF expression, as previously reported. Conclusions Although both LSD1 and DNMT1 are reported to be components of the DRED complex and are proposed to be jointly responsible for epigenetically modifying the gamma globin promoter to silence HbF expression, inhibition of the two proteins had different outcomes on HbF expression. DNMT1 inhibition upregulated HbF expression to a similar extent as pomalidomide (currently in Phase 1 clinical trials for HbF induction), whereas LSD1 inhibition impaired erythroid differentiation and hemoglobinization. These results suggest that the mechanism of gamma globin silencing and the proposed role of the DRED complex require further evaluation. Furthermore, this work also suggests that LSD1 inhibition is not a therapeutic strategy for HbF induction in patients with sickle cell disease or beta thalassemia. Disclosures: Arvedson: Amgen: Employment. Tran:Amgen: Employment. Ross:Amgen: Employment. Yoder:Amgen: Employment. Hertz:Amgen: Employment. Hale:Amgen: Employment. Eschelbach:Amgen: Employment. Dineen:Amgen: Employment. Matyas:Amgen: Employment. Hartley:Amgen: Employment. Morgenstern:Amgen: Employment. Winters:Amgen: Employment. Cindy:Amgen: Employment. Molineux:Amgen: Employment. Coxon:Amgen: Employment.

scholarly journals Complementary Base Editing Approaches for the Treatment of Sickle Cell Disease and Beta Thalassemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3352-3352 ◽  
Author(s):  
Ling Lin ◽  
Adrian P. Rybak ◽  
Conrad Rinaldi ◽  
Jonathan Yen ◽  
Yanfang Fu ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Base Editing ◽  
Gamma Globin

Sickle cell disease (SCD) and Beta thalassemia are disorders of beta globin production and function that lead to severe anemia and significant disease complications across a multitude of organ systems. Autologous transplantation of hematopoietic stem cells engineered through the upregulation of fetal hemoglobin (HbF) or correction of the beta globin gene have the potential to reduce disease burden in patients with beta hemoglobinopathies. Base editing is a recently developed technology that enables precise modification of the genome without the introduction of double strand DNA breaks. Gamma globin gene promoters were comprehensively screened with cytosine and adenine base editors (ABE) for the identification of alterations that would derepress HbF. Three regions were identified that significantly upregulated HbF, and the most effective nucleotide residue conversions are supported by natural variation seen in patients with hereditary persistence of fetal hemoglobin (HPFH). ABEs have been developed that significantly increase the level of HbF following nucleotide conversion at key regulatory motifs within the HBG1 and HBG2 promoters. CD34+ hematopoietic stem and progenitor cells (HSPC) were purified at clinical scale and edited using a process designed to preserve self-renewal capacity. Editing at two independent sites with different ABEs reached 94 percent and resulted in up to 63 percent gamma globin by UPLC. The levels of HbF observed should afford protection to the majority of SCD and Beta thalassemia patients based on clinical observations of HPFH and non-interventional therapy that links higher HbF dosage with milder disease (Ngo et al, 2011 Brit J Hem; Musallam et al, 2012 Blood). Directly correcting the Glu6Val mutation of SCD has been a recent goal of genetic therapies designed for the SCD population. Current base editing technology cannot yet convert mutations like those that result from the A-T transversion in sickle beta globin; however, ABE variants have been designed to recognize and edit the opposite stranded adenine residue of valine. This results in the conversion of valine to alanine and the production of a naturally occurring variant known as Hb G-Makassar. Beta globin with alanine at this position does not contribute to polymer formation, and patients with Hb G-Makassar present with normal hematological parameters and red blood cell morphology. SCD patient fibroblasts edited with these ABE variants achieve up to 70 percent conversion of the target adenine. CD34 cells from healthy donors were then edited with a lead ABE variant, targeting a synonymous mutation in an adjacent proline that resides within the editing window and serves as a proxy for editing the SCD mutation. The average editing frequency was 40 percent. Donor myeloid chimerism documented at these levels in the allogeneic transplant setting exceeds the 20 percent that is required for reversing the sickle phenotype (Fitzhugh et al, 2017 Blood). These next generation editing approaches provide a promising new modality for treating patients with Beta thalassemia and SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sickle - Cell Disease

2020 ◽  
pp. 1-2
Author(s):  
Shriya Phadnis ◽  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
The Body ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Tissue Ischemia ◽  
Nitric Oxide Signaling ◽  
Cause Of Deaths

Sickle cell disease is a common inherited, multisystem, monogenic disorder of red blood cells (erythrocytes) caused due to polymorphic changes in hemoglobin. The most commonly known condition; Sickle cell anemia wherein there aren’t enough healthy RBCs to carry adequate oxygen throughout the body is considered to be a common form if Sickle-cell disease. Other type of Sickle cell disease is Hemoglobin SC disease (HbSC) caused due to inheritance of beta s and beta c alleles. The third type of such disease is HbS thalassemia caused due to beta-thalassemia mutation in the beta-globin gene leading to Sickle hemoglobin (HbS). Polymerization of HbS due to presence of fetal hemoglobin in the erythrocytes that in turn reduces the concentration of HbS which becomes the prominent determinant to check the severity of the disease. Reduced concentrations of HbS also reduce hemolysis that prevents acute vaso- occlusion. This pain is caused as the irregular shaped RBCs and WBCs get entrapped in the small blood vessels causing vascular obstruction and tissue ischemia. HbS polymerization can also lead to hemolytic anemia which is a state where in rate of RBC destruction is faster than formation; such patients are likely to develop vasculopathy. During the process of hemolysis, hemoglobin is released into plasma that inhibits endothelial nitric oxide signaling causing endothelial cell dysfunction. Hemolysis is also associated with formation of erythrocyte microvesicles that acts as a activator of tissue factor. Malaria is considered to cause HbS. Sickle cell disease is found to be highest in the African continent mostly affecting the new borns. The cause of deaths is hug in Africa due to poor diagnostic facilities. Measures taken against H influenzae and S pneumoniae that is profoundly detected in African children with Sickle cell disease can help reduce the disease proximity. Implementation of early life screening can thereby be effective in this case.

The Relationship Between Pre-Pregnancy Sickle Cell Disease-Specific Complications and Maternal and Fetal Outcomes in Sickle Cell Disease Pregnancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4848-4848
Author(s):  
Dalal H. Mulla-Ali ◽  
Kevin H.M. Kuo ◽  
Mathew Sermer ◽  
Anne Mcleod
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Fetal Outcomes ◽  
On Demand ◽  
Fetal Complications ◽  
History Of ◽  
Antepartum Complications

Abstract Abstract 4848 Introduction: Patients with sickle cell disease (SCD) have worse maternal and fetal outcomes compared to the general population, and experience antepartum complications unique to SCD patients, including painful vasoocclusive crises (VOC), acute chest syndrome (ACS), stroke and symptomatic anemia. The relationship between pre-pregnancy SCD-specific complications and maternal/fetal outcomes and antepartum complications has not been explored. We hypothesize that increased rates of SCD-specific complications are associated with increased rates of antepartum SCD-specific complications and worsened maternal and fetal outcomes. We further hypothesize that elevation in fetal hemoglobin is associated with improved maternal/fetal outcomes. Materials and Methods: We conducted a retrospective review of patients with SCD (SS, SC, S/beta-thalassemia) whose pregnancies were managed at the Mount Sinai Hospital (MSH), a high risk obstetrics care institution in Ontario, Canada, between January 1st, 1999 and June 30th, 2009 based on the institution's electronic and paper-based medical records. Patients were jointly managed by a hematologist specialized in hemoglobinopathies and an obstetrician specialized in high risk obstetric care. We compared the pre-pregnancy and antepartum rates of SCD-specific complications (painful VOC, ACS, stroke, and on-demand transfusion requirements). Pre-pregnancy fetal hemoglobin level was analyzed according to the presence or absence of maternal/fetal complications (expressed as an aggregate of preterm delivery, placental insufficiency, low birth weight (<2500 g), the need of emergent Caesarian section, fetal anomalies and fetal death). The t-test was used to compare means of the two groups. Fisher's exact test was used to compare categorical frequency data. An alpha value of 0.05 was chosen as the level of significance. Results and Discussion: We identified 22 pregnancies in 22 patients with SCD, 4 patients had not delivered at the time of censor. Fourteen patients were HbSS, 7 were HbSC, 1 was HbS/beta-thalassemia. Mean maternal age was 31.1 years. Mean gestational age at delivery was 37 weeks (95% CI 36 to 38 weeks) and 5 (23%) were preterm (< 37 weeks). Eleven of the 18 deliveries (61%) were by Caesarian section and 7 were performed on an emergent basis (4 due to fetal distress and 3 due to failure to progress). Three (17%) were low birth weight (< 2500 g) and 2 (11%) were intrauterine growth restricted. Maternal and fetal outcomes and rates of antepartum complications were similar to the existing literature. There was no association between prior history of ACS and having an episode of ACS during pregnancy. A history of painful VOC was associated with having at least one episode of painful VOC during pregnancy (P = 0.0433). Pre-pregnancy history of on-demand red cell transfusion was also associated with the need of at least one unit of transfusion during pregnancy (P = 0.0048). However, the frequency and time of first painful VOC during pregnancy were not associated with worsened maternal/fetal outcome. There was no association between fetal hemoglobin level and antepartum rates of painful VOC (P = 0.4867), ACS (P = 0.3702), and maternal/fetal complications (P = 0.2489). The results suggest that patients with a history of painful VOC may be predisposed to having painful VOC during pregnancy. Similarly, patients with a history of on-demand transfusion may need transfusion during pregnancy. The present study is limited by small sample size and its single-centered and retrospective nature. Further observation studies with larger sample size are required to prospectively validate these results. Disclosures: Kuo: Novartis Canada: Research Funding.

Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 58-62 ◽  
Author(s):  
Hassana Fathallah ◽  
George F. Atweh
Keyword(s):  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Approach ◽  
Therapeutic Option ◽  
Fetal Hemoglobin ◽  
Mechanisms Of Action ◽  
Cell Disease ◽  
Sickle Hemoglobin ◽  
Considerable Promise

Abstract Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in patients with hemoglobin disorders. In sickle cell disease (SCD), an increase in HbF inhibits the polymerization of sickle hemoglobin and the resulting pathophysiology. Hydroxyurea, an inducer of HbF, has already been approved for the treatment of patients with moderate and/or severe SCD. Recent clinical trials with other pharmacological inducers of HbF, such as butyrate and decitabine, have shown considerable promise. In this chapter, we highlight the important clinical trials with pharmacological inducers of HbF, discuss their mechanisms of action and speculate about the future of this therapeutic approach in the treatment of patients with SCD.

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