Development of gene therapy for blood disorders: an update

Nienhuis, Arthur W.

doi:10.1182/blood-2013-04-453209

Cited by 45 publications

(40 citation statements)

References 107 publications

(125 reference statements)

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“…2,7,8,29 Successful transduction of HSCs faces the limitations www.moleculartherapy.org of starting with a finite and rare cell population (i.e., HSCs after a bone marrow harvest procedure) and then maintaining the transduced cells in a primitive state resulting in the long-term hematopoiesis required for the resolution of thalassemia. Methods that focus on expanding transduced HSCs could improve the efficiency of the corrective gene transfer by increasing the number of HSCs available for transplantation as well as increasing the number of corrected HSCs after transduction.…”

Section: Discussionmentioning

confidence: 99%

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Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

et al. 2017

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Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7] The first clinical trial for b-thalassemia was initiated in 2007. 8 One of three patients demonstrated clinical benefit and became transfusion independent with stable hemoglobin (Hb) of greater than 8 g/dL.…”

Section: Introductionmentioning

confidence: 99%

Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

et al. 2017

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“…GFP mRNA expression and AAV genomes in mouse liver were quantified by SYBR-green qPCR (threshold cycle [2 Ϫ⌬⌬CT ] method) with murine glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a control, using primers hybridizing within the GFP coding region and CMV promoter, respectively. Primer sequences were as follows: GFP fwd, 5=-GCA CGA CTT CTT CAA GTC CGC CAT GCC-3=; GFP rvs, 5=-GCG GAT CTT GAA GTT CAC CTT GAT GCC-3=; GAPDH fwd, 5=-CTG CGG AAA TGG TGT GAT CTT CCC CAA GGG-3=; GAPDH rvs, 5=-AGG GAG CTC CAT TCA TGT GCT AAA CAG GCC-3=; CMV fwd, 5=-ACG CCA ATA GGG ACT TTC CA-3=; and CMV rvs, 5=-TAG GGG GCG TAC TTG GCA TA-3=.…”

Section: Micementioning

confidence: 99%

“…Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) vectors have shown promise in clinical trials for treatment of a wide variety of diseases (1,2). Both vectors, when injected intravenously into mice, exhibit transgene expression in liver (3)(4)(5).…”

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confidence: 99%

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

Zaiss

Foley

Lawrence

et al. 2016

J Virol

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Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. A better understanding of how viral vectors enter cells in vivo is critical to improve their therapeutic use. Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) vectors have shown promise in clinical trials for treatment of a wide variety of diseases (1, 2). Both vectors, when injected intravenously into mice, exhibit transgene expression in liver (3-5). Heparan sulfate proteoglycans (HSPGs) are the primary receptors currently thought to facilitate AAV2 and Ad5 entry into hepatocytes (6-8).HSPGs are present both on the cell surface and in the extracellular matrix (9, 10). They consist of a protein core posttranslationally modified to contain heparan sulfate (HS) chains (11). HS biosynthesis occurs by polymerization of alternating glucuronic acid and N-acetylglucosamine residues (12-14), catalyzed by an enzyme complex composed of EXT1 and EXT2 (15). EXT1 and EXT2 are essential molecules required for HS synthesis; cells lacking either molecule do not synthesize HS (16,49).AAV2 binds directly to cell surface HSPGs via an HS-binding motif on the virus capsid (3,17,18). AAV capsid modifications that alter the cluster of positive amino acids that constitute the HS binding motif abrogate liver transduction (3,19,20), suggesting that the ability of the capsid to bind to HS is critical for AAV2 liver transduction in vivo. In contrast, Ad5 binding to HSPGs requires the presence of blood coagulation factor X (FX), which binds to the Ad5 hexon when the virus comes in contact with blood (7,(21)(22)(23). The interaction of Ad.FX and HS is mediated by electrostatic interactions between the heparin binding exosite of the FX serine protease domain and the sulfate groups of HS (6,(23)(24)(25). FX is required for Ad5 transduction in vivo in wild-type mice. In the absence of FX, or when viruses with mutant hexon proteins unable to bind FX are used, Ad5 liver transduction is essentially completely abrogated (7, 21-23, 26, 27).

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“…51 For those disorders where the defect is due to mutations in single genes that affect hemoglobin synthesis, the approach has been to introduce a normal…”

Section: Gene Therapy For B-thalassemia Majormentioning

confidence: 99%

Cure for thalassemia major – from allogeneic hematopoietic stem cell transplantation to gene therapy

Srivastava

Shaji

2016

Haematologica

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A llogeneic hematopoietic stem cell transplantation has been well established for several decades as gene replacement therapy for patients with thalassemia major, and now offers very high rates of cure for patients who have access to this therapy. Outcomes have improved tremendously over the last decade, even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent, with a >90% survival rate, but for the best results, hematopoietic stem cell transplantation should be offered early, before any end organ damage occurs. However, access to this therapy is limited in more than half the patients by the lack of suitable donors. Inadequate hematopoietic stem cell transplantation services and the high cost of therapy are other reasons for this limited access, particularly in those parts of the world which have a high prevalence of this condition. As a result, fewer than 10% of eligible patients are actually able to avail of this therapy. Other options for curative therapies are therefore needed. Recently, gene correction of autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the b-globin mutation or disrupt the BCL11A gene to increase fetal hemoglobin production has also been reported, and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world will remain a challenge.

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Development of gene therapy for blood disorders: an update

Cited by 45 publications

References 107 publications

Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

Cure for thalassemia major – from allogeneic hematopoietic stem cell transplantation to gene therapy

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