Prolonged expression of a lysosomal enzyme in mouse liver after <i>Sleeping Beauty</i> transposon‐mediated gene delivery: implications for non‐viral gene therapy of mucopolysaccharidoses

Aronovich, Elena L.; Bell, Jason; Belur, Lalitha R.; Günther, Roland; Koniar, Brenda; Erickson, David C.C.; Schachern, Patricia A.; Matise, Ilze; McIvor, R. Scott; Whitley, Chester B.; Hackett, Perry B.

doi:10.1002/jgm.1028

Cited by 102 publications

(134 citation statements)

References 47 publications

(83 reference statements)

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“…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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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: 99%

Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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“…A great advantage of DNA-based elements is the simplicity and safety of their usage. Elements of this type currently used for mammals include the naturally occurring elements Tol2 from the medaka fish (Koga et al 2003;Koga et al 2006) and piggyBac from a moth (Fraser et al 1996;Wilson et al 2007), as well as the resurrected element Sleeping Beauty from salmonid fishes (Ivics et al 1997;Aronovich et al 2007). We recently found another element, Tol1 of the medaka fish, which has the potential for development as a genetic tool.…”

Section: Introductionmentioning

confidence: 99%

The Tol1 element of medaka fish is transposed with only terminal regions and can deliver large DNA fragments into the chromosomes

et al. 2007

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Tol1 is an active DNA-based transposable element residing in the genome of the medaka fish Oryzias latipes. This element belongs to the hAT transposable element family, of which complete copies have relatively long sequences. In addition, we found that Tol1 elements as long as 18 and 20 kb occur in the medaka fish genome. These facts suggest that Tol1 is suitable for carrying large DNA fragments as a gene transfer vector. Focusing on this, we conducted two kinds of manipulations of the element. The first was to eliminate internal regions dispensable for transposition. It was revealed that a Tol1 element consisting of 157-bp left-and 106-bp right-terminal regions could be transposed without a loss of transposition efficiency. Next, we prepared long Tol1 elements by incorporating unrelated DNA fragments into this short Tol1 clone and examined their transposition efficiencies. The transposition frequency decreased as the element size increased. The longest Tol1 element we examined measured 22.1 kb, and its transposition frequency was approximately one fifth that of a 2.1-kb element. However, this frequency was still significantly higher than that of a random integration of DNA into the chromosomes. The element size of 22.1 kb is the longest ever reported for DNA-based elements currently used for mammals. Thus, Tol1 is a superior genetransfer vector with a large cargo capacity.

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“…The serum level of GUSB obtained 30 days after injection was higher than those described earlier with Sleeping Beauty transposon-mediated gene delivery. 18 Furthermore, GUSB activity was still detected 30 and 60 days after gene transfer in almost all the tissues. This expression maintenance could be attribuated to the lack of a strong immune response directed toward bglucuronidase, as confirmed by ELISA assay performed on several injected MPS VII mice at different times post injection (data not shown).…”

Section: Discussionmentioning

confidence: 95%

“…This expression maintenance could be attribuated to the lack of a strong immune response directed toward bglucuronidase, as confirmed by ELISA assay performed on several injected MPS VII mice at different times post injection (data not shown). Unlike the earlier study of Aronovich et al 18 in which the human GUSB gene was used, in this study we used the murine GUSB cDNA. First, adult MPS VII mice have a known defect in immunity 33 and might not generate a strong immune response to a foreign protein in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, this non-viral approach had a beneficial effect on the disease as it corrected secondary enzymatic abnormalities and reduced GAG storage, not only in several peripheral tissues but also in brain. To our knowledge, this is one of the first demonstration 18 of a non-viral strategy providing successful replacement gene therapy for Sly disease and more generally for a neurological form of MPS.…”

Section: Introductionmentioning

confidence: 90%

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Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery

et al. 2009

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Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the acid hydrolase b-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans (GAGs) within multiple organs, including the brain. Using this animal model, we compared two plasmid gene administration techniques: muscle electrotransfer and liver-directed transfer using hydrodynamic injection. We have evaluated both the expression kinetics and the biodistribution of b-glucuronidase activity after gene transfer, as well as the correction of biochemical abnormalities in various organs. This study shows that MPS VII mice treated with a plasmid-bearing mouse b-glucuronidase cDNA, acquire the ability to produce the b-glucuronidase enzyme for an extended period of time.The liver seemed to be more appropriate than the muscle as a target organ to enable enzyme secretion into the systemic circulation. A beneficial effect on the MPS VII pathology was also observed, as liver-directed gene transfer led to the correction of secondary enzymatic elevations and to the reduction of GAGs storage in peripheral tissues and brain, as well as to histological correction in many tissues. This work is one of the first examples showing that non-viral plasmid DNA delivery can lead to improvements in both peripheral and brain manifestations of MPS VII disease. It confirms the potential of non-viral systemic gene transfer strategy in neurological lysosomal disorders.

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Prolonged expression of a lysosomal enzyme in mouse liver after Sleeping Beauty transposon‐mediated gene delivery: implications for non‐viral gene therapy of mucopolysaccharidoses

Abstract: Background-The Sleeping Beauty (SB) transposon system is a non-viral vector system that can integrate precise sequences into chromosomes. We evaluated the SB transposon system as a tool for gene therapy of mucopolysaccharidosis (MPS) types I and VII.

Cited by 102 publications

References 47 publications

Therapies for the bone in mucopolysaccharidoses

Therapies for the bone in mucopolysaccharidoses

The Tol1 element of medaka fish is transposed with only terminal regions and can deliver large DNA fragments into the chromosomes

Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery

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