Induction of Fetal Hemoglobin<i>In Vivo</i>Mediated by a Synthetic<i>γ</i>-Globin Zinc Finger Activator

Costa, Flavia C; Fedosyuk, Halyna; Neades, Renee; Rios, Johana Bravo de los; Barbas, Carlos F.; Peterson, Kenneth R.

doi:10.1155/2012/507894

Cited by 32 publications

(21 citation statements)

References 33 publications

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“…Overexpression of endogenous γ‐globin has been induced in CD34+ cells from thalassemia patients with the use of lentiviral vectors expressing a zinc finger protein (GG1‐VP64) which interacts with the promoter of γ‐globin gene . Silencing of γ‐globin repressors, such as BCL11A, with lentiviruses carrying sequences of microRNAs has been shown to increase HbF production .…”

Section: New Therapeutic Approaches In Preclinical Development For β‐mentioning

confidence: 99%

2017 Clinical trials update in new treatments of β‐thalassemia

et al. 2016

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The underlying basis of b-thalassemia pathology is the diminished b-globin synthesis leading to a-globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress-induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF-b ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRIeIF2aP, Prx2, Hsp70, and PK anti-oxidant systems and inhibitors of HO-1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the g-or b-globin gene are novel and promising experimental gene therapy approaches for b-thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying b-thalassemia in relation to the development of new therapies and an update is given both at the pre-clinical and clinical level.

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Section: New Therapeutic Approaches In Preclinical Development For β‐mentioning

confidence: 99%

2017 Clinical trials update in new treatments of β‐thalassemia

et al. 2016

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“…Importantly, our results contribute to demonstrate that artificial zinc finger transcription factors may be a class of therapeutic reagents for treatment of crucial inherited diseases [38]. …”

Section: Discussionmentioning

confidence: 99%

UtroUp is a novel six zinc finger artificial transcription factor that recognises 18 base pairs of the utrophin promoter and efficiently drives utrophin upregulation

et al. 2013

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BackgroundDuchenne muscular dystrophy (DMD) is the most common X-linked muscle degenerative disease and it is due to the absence of the cytoskeletal protein dystrophin. Currently there is no effective treatment for DMD. Among the different strategies for achieving a functional recovery of the dystrophic muscle, the upregulation of the dystrophin-related gene utrophin is becoming more and more feasible.ResultsWe have previously shown that the zinc finger-based artificial transcriptional factor “Jazz” corrects the dystrophic pathology in mdx mice by upregulating utrophin gene expression. Here we describe a novel artificial transcription factor, named “UtroUp”, engineered to further improve the DNA-binding specificity. UtroUp has been designed to recognise an extended DNA target sequence on both the human and mouse utrophin gene promoters. The UtroUp DNA-binding domain contains six zinc finger motifs in tandem, which is able to recognise an 18-base-pair DNA target sequence that statistically is present only once in the human genome. To achieve a higher transcriptional activation, we coupled the UtroUp DNA-binding domain with the innovative transcriptional activation domain, which was derived from the multivalent adaptor protein Che-1/AATF. We show that the artificial transcription factor UtroUp, due to its six zinc finger tandem motif, possesses a low dissociation constant that is consistent with a strong affinity/specificity toward its DNA-binding site. When expressed in mammalian cell lines, UtroUp promotes utrophin transcription and efficiently accesses active chromatin promoting accumulation of the acetylated form of histone H3 in the utrophin promoter locus.ConclusionsThis novel artificial molecule may represent an improved platform for the development of future applications in DMD treatment.

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“…Gg1-VP64 was then tested in early erythroid progenitors derived from cytokine-mobilized adult peripheral blood CD34 + cells and this artificial transcription factor was able to increase HbF levels from 2% to 20% of the total hemoglobin which can be therapeutically applicable (Wilber et al 2010). Costa et al further showed 5-fold induction of HbF in gg1-VP64 β-YAC double-transgenic (bigenic) mice, demonstrating its efficacy in vivo (Costa et al 2012). …”

Section: Genome Editing To Induce Fetal Hemoglobin Expressionmentioning

confidence: 99%

Use of genome-editing tools to treat sickle cell disease

2016

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Recent advances in genome editing techniques have made it possible to modify any desired DNA sequence by employing programmable nucleases. These next generation genome-modifying tools are the ideal candidates for therapeutic applications, especially for the treatment of genetic disorders like sickle cell disease (SCD). SCD is an inheritable monogenic disorder which is caused by a point mutation in the β-globin gene. Substantial success has been achieved in the development of supportive therapeutic strategies for SCD but unfortunately there is still a lack of long-term universal cure. The only existing curative treatment is based on allogeneic stem cell transplantation from healthy donors; however, this treatment is applicable to a limited number of patients only. Hence, a universally applicable therapy is highly desirable. In this review we will discuss the three programmable nucleases that are commonly used for genome editing purposes: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9). We will continue by exemplifying uses of these methods to correct the sickle cell mutation. Additionally, we will present induction of fetal globin expression as an alternative approach to cure sickle cell disease. We will conclude by comparing the three methods and explaining the concerns about their use in therapy.

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Induction of Fetal HemoglobinIn VivoMediated by a Syntheticγ-Globin Zinc Finger Activator

Cited by 32 publications

References 33 publications

2017 Clinical trials update in new treatments of β‐thalassemia

2017 Clinical trials update in new treatments of β‐thalassemia

UtroUp is a novel six zinc finger artificial transcription factor that recognises 18 base pairs of the utrophin promoter and efficiently drives utrophin upregulation

Use of genome-editing tools to treat sickle cell disease

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