Systemic Correction of Storage Disease in MPS I NOD/SCID Mice Using the Sleeping Beauty Transposon System

Aronovich, Elena L.; Bell, Jason; Khan, Shaukat; Belur, Lalitha R.; Günther, Roland; Koniar, Brenda; Schachern, Patricia A.; Parker, Josh; Carlson, Cathy S.; Whitley, Chester B.; McIvor, R. Scott; Gupta, Pankaj; Hackett, Perry B.

doi:10.1038/mt.2009.87

Cited by 84 publications

(117 citation statements)

References 49 publications

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“…plasmids and transposons) have shown improvements in some manifestations of the disease, but the low-level and short-term expression limits the impact of these vectors in bone lesions. The sleeping beauty transposon system resulted in a significant increase in IDUA activity in several tissues, normalization of GAG storage in those tissues, and reduction of hepatomegaly [118]. In addition, sleeping beauty-based therapy corrected thickening of the bone of the zygomatic arch and growth plate abnormalities in femur and tibia; but consistent positive effects were not observed in cortical thickness or diameters of mid-diaphyseal bone areas [118].…”

Section: Gene Therapymentioning

confidence: 96%

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Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required.Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life.This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.

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Section: Gene Therapymentioning

confidence: 96%

“…Here we summarize the recent achievements for bone lesions in gene therapies of animal models of MPS. [115,116], sleeping beauty transposon [117,118], gamma-retrovirus [58,[119][120][121], lentivectors [122], and adenoassociated virus (AAV) vectors [123,124]. Non-viral vectors (i.e.…”

Section: Gene Therapymentioning

confidence: 99%

Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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“…This procedure has been successfully applied to confer a therapeutic benefit in several animal models of human diseases, including hemophilia B after delivery of human clotting factor IX (FIX) as a therapeutic gene product in FIX-deficient mice (Yant et al, 2000) and tyrosinemia after hydrodynamic delivery of a fumarylacetoacetate hydrolase (FAH)-encoding SB transposon vector into the livers of FAH-deficient mice that showed selective outgrowth of genetically corrected hepatocytes (Montini et al, 2002). Additional, successful preclinical testing of the SB system has been established in disease models for hemophilia A (Ohlfest et al, 2005b) and mucopolysaccharidosis (Aronovich et al, , 2009.…”

Section: Fig 2 Expression Cassettes Delivered By Sleeping Beauty Trmentioning

confidence: 99%

“…However, with careful promoter choice, several studies have established that SB-mediated transposition provides long-term expression in vivo, as discussed previously. Notably, stable transgene expression from SB vectors was seen in mice after gene delivery in the liver (Yant et al, 2000;Ohlfest et al, 2005b;Aronovich et al, 2009;Kren et al, 2009), lung (Belur et al, 2003;L. Liu et al, 2006b), brain (Ohlfest et al, 2005a), and blood after hematopoietic reconstitution in vivo Xue et al, 2009).…”

Section: Transgene Expressionmentioning

confidence: 99%

“…Liu et al, 2006b;Kren et al, 2009;Hausl et al, 2010) (Aronovich et al, , 2009, cancer (Ohlfest et al, 2005a;Peng et al, 2009;Jin et al, 2011), and type 1 diabetes (He et al, 2004). In addition, important steps have been made toward SB-mediated gene transfer in the lung for potential therapy of a 1 -antitrypsin deficiency, cystic fibrosis, and a variety of cardiovascular diseases (Belur et al, 2003;Liu et al, 2004).…”

Section: Future Considerations/outlookmentioning

confidence: 99%

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Nonviral Gene Delivery with the Sleeping Beauty Transposon System

Ivics

Izsvák²

2011

Human Gene Therapy

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Effective gene therapy requires robust delivery of therapeutic genes into relevant target cells, long-term gene expression, and minimal risks of secondary effects. Nonviral gene transfer approaches typically result in only short-lived transgene expression in primary cells, because of the lack of nuclear maintenance of the vector over several rounds of cell division. The development of efficient and safe nonviral vectors armed with an integrating feature would thus greatly facilitate clinical gene therapy studies. The latest generation transposon technology based on the Sleeping Beauty (SB) transposon may potentially overcome some of these limitations. SB was shown to provide efficient stable gene transfer and sustained transgene expression in primary cell types, including human hematopoietic progenitors, mesenchymal stem cells, muscle stem/progenitor cells (myoblasts), induced pluripotent stem cells, and T cells. These cells are relevant targets for stem cell biology, regenerative medicine, and gene-and cell-based therapies of complex genetic diseases. Moreover, the first-in-human clinical trial has been launched to use redirected T cells engineered with SB for gene therapy of B cell lymphoma. We discuss aspects of cellular delivery of the SB transposon system, transgene expression provided by integrated transposon vectors, target site selection of the transposon vectors, and potential risks associated with random genomic insertion.

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Translating Sleeping Beauty transposition into cellular therapies: Victories and challenges

et al. 2010

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Recent results confirm that long-term expression of therapeutic transgenes can be achieved by using a transposon-based system in primary stem cells and in vivo. Transposable elements are natural DNA transfer vehicles that are capable of efficient genomic insertion. The latest generation, Sleeping Beauty transposon-based hyperactive vector (SB100X), is able to address the basic problem of non-viral approaches – that is, low efficiency of stable gene transfer. The combination of transposon-based non-viral gene transfer with the latest improvements of non-viral delivery techniques could provide a long-term therapeutic effect without compromising biosafety. The new challenges of pre-clinical research will focus on further refinement of the technology in large animal models and improving the safety profile of SB vectors by target-selected transgene integration into genomic “safe harbors.” The first clinical application of the SB system will help to validate the safety of this approach.

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Systemic Correction of Storage Disease in MPS I NOD/SCID Mice Using the Sleeping Beauty Transposon System

Cited by 84 publications

References 49 publications

Therapies for the bone in mucopolysaccharidoses

Therapies for the bone in mucopolysaccharidoses

Nonviral Gene Delivery with the Sleeping Beauty Transposon System

Translating Sleeping Beauty transposition into cellular therapies: Victories and challenges

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