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Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.

ABSTRACT: Persistence of human fetal hemoglobin (HbF, ?(2)?(2)) in adults lessens the severity of sickle cell disease (SCD) and the ?-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of ?-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.

SUBMITTER: Xu J

PROVIDER: S-EPMC3746545 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.

Xu Jian J Peng Cong C Sankaran Vijay G VG Shao Zhen Z Esrick Erica B EB Chong Bryan G BG Ippolito Gregory C GC Fujiwara Yuko Y Ebert Benjamin L BL Tucker Philip W PW Orkin Stuart H SH

Science (New York, N.Y.) 20111013 6058

Persistence of human fetal hemoglobin (HbF, α(2)γ(2)) in adults lessens the severity of sickle cell disease (SCD) and the β-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of γ-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD trans ...[more]

PMID: 21998251

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MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease.

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g(HbF): a genetic model of fetal hemoglobin in sickle cell disease.

Project description:Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and is associated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci would specifically address the benefits of HbF increases in patients. Here, we have applied statistical methods using the most representative variants: rs1427407 and rs6545816 in BCL11A, rs66650371 (3-bp deletion) and rs9376090 in HMIP-2A, rs9494142 and rs9494145 in HMIP-2B, and rs7482144 (Xmn1-HBG2 in the ?-globin locus) to create g(HbF), a genetic quantitative variable for HbF in SCD. Only patients aged ?5 years with complete genotype and HbF data were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbS?0 thalassemia formed the "discovery" cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers (rs6545816, rs1427407, rs66650371, and rs7482144) each independently contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability (r2) in the HbSS or HbS?0 patients. The model was replicated with consistent r2 in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. g(HbF), our 4-variant model, provides a robust approach to account for the genetic component of HbF in SCD and is of potential utility in sickle genetic and clinical studies.

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The Genetic and Clinical Significance of Fetal Hemoglobin Expression in Sickle Cell Disease.

Project description:Sickle cell disease (SCD) is phenotypically heterogeneous. One major genetic modifying factor is the patient's fetal hemoglobin (HbF) level. The latter is determined by the patient's β-globin gene cluster haplotype and cis- and trans-acting single nucleotide polymorphisms (SNPs) at other distant quantitative trait loci (QTL). The Arab/India haplotype is associated with persistently high HbF levels and also a relatively mild phenotype. This haplotype carries the Xmn1 (C/T) SNP, rs7482144, in the HBG2 locus. The major identified trans-acting QTL contain SNPs residing in the BCL11A on chromosome 2 and the HMIP locus on chromosome 6. These collectively account for 15-30% of HbF expression in different world populations and in patients with SCD or β-thalassemia. Patients with SCD in Kuwait and Eastern Saudi Arabia uniformly carry the Arab/India haplotype, but despite this, the HbF and clinical phenotypes show considerable heterogeneity. Pain episodes and avascular necrosis of the femoral head are particularly common, but severe bacterial infections, stroke, priapism, and leg ulcers are uncommon. Moreover, the HbF modifiers appear to be different; the reported BCL11A and HMIP SNPs appear to play insignificant roles. There are probably novel modifiers to be discovered in this population. This review examines the common clinical phenotypes in Kuwaiti patients with elevated HbF and the available information on HbF modifiers. The response of the patients to hydroxyurea is discussed. The presentation of patients with other sickle compound heterozygotes (Sβthal and HbSD), vis-à-vis their HbF levels, is also addressed critically.

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CRISPR-Cas9 to induce fetal hemoglobin for the treatment of sickle cell disease.

Project description:Genome editing is potentially a curative technique available to all individuals with β-hemoglobinopathies, including sickle cell disease (SCD). Fetal hemoglobin (HbF) inhibits sickle hemoglobin (HbS) polymerization, and it is well described that naturally occurring hereditary persistence of HbF (HPFH) alleviates disease symptoms; therefore, reawakening of developmentally silenced HbF in adult red blood cells (RBCs) has long been of interest as a therapeutic strategy. Recent advances in genome editing platforms, particularly with the use of CRISPR-Cas9, have paved the way for efficient HbF induction through the creation of artificial HPFH mutations, editing of transcriptional HbF silencers, and modulating epigenetic intermediates that govern HbF expression. Clinical trials investigating BCL11A enhancer editing in patients with β-hemoglobinopathies have demonstrated promising results, although follow-up is short and the number of patients treated to date is low. While practical, economic, and clinical challenges of genome editing are well recognized by the scientific community, potential solutions to overcome these hurdles are in development. Here, we review the recent progress and obstacles yet to be overcome for the most effective and feasible HbF reactivation practice using CRISPR-Cas9 genome editing as a curative strategy for patients with SCD.

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