Wake-up Sleepy Gene: Reactivating Fetal Globin for β-Hemoglobinopathies

Wienert, Beeke; Martyn, Gabriella E.; Funnell, Alister P. W.; Quinlan, Kate; Crossley, Merlin

doi:10.1016/j.tig.2018.09.004

Cited by 95 publications

(83 citation statements)

References 104 publications

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“…Point mutations or small deletions in the proximal fetal γ-globin gene promoter lead to nd-HPFH. However, as individuals with nd-HPFH are usually healthy, HPFH appears to be a natural and benign mechanism to elevate HbF expression in adults [13]. Although considerable research has recently been focused on nd-HPFH in efforts to reactivate the fetal γ-globin gene in adulthood for β-thalassemia treatment [14][15][16], there is little information regarding the prevalence and hematologic characteristics of nd-HPFH in China, which would be helpful for precise genetic counseling.…”

Section: Introductionmentioning

confidence: 99%

Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China

Jiang

Zuo

et al. 2020

BMC Med Genet

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Background: Individuals with δβ-thalassemia/HPFH and β-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δβ-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. Methods: A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level ≥ 5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) was used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene was performed for all those subjects. Results: A total of 654 individuals had hemoglobin (HbF) levels≥5, and 0.12% of the couples were found to be heterozygous for HPFH/δβ-thalassemia, including Chinese G γ ( A γδβ) 0 -thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore-Boston-Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying β-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 55cases of nondeletional-HPFH (nd-HPFH), including 54 with Italian nd-HPFH and one with the A γ-197C-T heterozygous state. It is difficult to discriminate between Chinese G γ ( A γδβ) 0 -thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. (Continued on next page)Conclusions: This study is the first to describe the familial prevalence of HPFH/δβ-thalassemia and the high-risk rate in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We also presented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for β-thalassemia intermedia.

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Section: Introductionmentioning

confidence: 99%

Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China

Jiang

Zuo

et al. 2020

BMC Med Genet

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“…While a number of studies have focused on utilizing genome editors to facilitate the correction of mutations in HBB, or to aid in site specific incorporation of an intact copy of HBB [74][75][76][77][78], others have focused on the editing ability alone. It has long been known that mutations resulting in persistence of fetal γ-globin expression (usually silenced at birth) reduce the debilitating effects of mutations in β-globin, including β-thalassemia and sickle cell disease [79]. Genome editing has been utilized to recreate the large deletion which causes Hereditary Persistence of Fetal Hemoglobin (HPFH), and hematopoietic stem cells that were Cas9-edited to create HPFH show increased expression of fetal γ-globin [80].…”

Section: Ex Vivo Cell Alteration and Infusion Trialsmentioning

confidence: 99%

Gene editing and CRISPR in the clinic: current and future perspectives

et al. 2020

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Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases which require cell modification in vivo. However, in vivo use of CRISPR technologies can be confounded by problems such as off-target editing, inefficient or off-target delivery, and stimulation of counterproductive immune responses. Current research addressing these issues may provide new opportunities for use of CRISPR in the clinical space. In this review, we examine the current status and scientific basis of clinical trials featuring ZFNs, TALENs, and CRISPR-based genome editing, the known limitations of CRISPR use in humans, and the rapidly developing CRISPR engineering space that should lay the groundwork for further translation to clinical application.

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“…Cell-intrinsic mimicry of fetal erythropoiesis is being actively explored as a potential route to treat a variety of globinopathies, including β-thalassemia and sickle cell disease (Platt et al, 1984;Wienert et al, 2018). These approaches stem from the observation that naturally occurring mutations which promote HbF re-expression can ameliorate β-globinopathy symptoms (Berry et al, 1992;Jacob and Raper, 1958).…”

Section: Introductionmentioning

confidence: 99%

“…These approaches stem from the observation that naturally occurring mutations which promote HbF re-expression can ameliorate β-globinopathy symptoms (Berry et al, 1992;Jacob and Raper, 1958). A variety of strategies for HbF re-expression are being pursued, including large deletions within the β-globin locus, mutations of the HBG1/2 promoter, and cell-specific reduction of the BCL11A repressor by enhancer editing (Sankaran, 2011;Wienert et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

ATF4 mediates fetal globin upregulation in response to reduced β-globin

Boontanrart

Banović

et al. 2020

Preprint

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Fetal development and anemias such as β-hemoglobinopathies trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin, which has suggested strategies to treat hemoglobinopathies such as thalassemia and sickle cell disease. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here we use CRISPR-Cas genome editing and CRISPRi transcriptional repression to model the stress caused by reduced levels of adult β-globin. We find that loss of β-globin is sufficient to induce widespread globin compensation, including robust re-expression of γ-globin. Timecourse RNA-seq of differentiating isogenic erythroid precursors identified the ATF4 transcription factor as a causal regulator of this response. ChIP-seq of multiple erythroid precursor genotypes and differentiation states revealed that β-globin knockout leads to reduced engagement of ATF4 targets involved in the unfolded protein response. This ATF4 program indirectly regulates the levels of BCL11A, a key repressor of γ-globin. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could be relevant for proposed gene editing strategies to treat hemoglobinopathies.

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Wake-up Sleepy Gene: Reactivating Fetal Globin for β-Hemoglobinopathies

Cited by 95 publications

References 104 publications

Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China

Molecular epidemiology and hematologic characterization of δβ-thalassemia and hereditary persistence of fetal hemoglobin in 125,661 families of greater Guangzhou area, the metropolis of southern China

Gene editing and CRISPR in the clinic: current and future perspectives

ATF4 mediates fetal globin upregulation in response to reduced β-globin

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