A tragic setback

Check, Erika

doi:10.1038/420116a

Cited by 265 publications

(108 citation statements)

References 7 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…Hepatocellular carcinomas and angiosarcomas occurred in adult MPS VII mice treated as newborns with the viral vector, which may integrate randomly into the mouse host genome. Insertional mutagenesis could explain the tumors seen in both the overexpressing transgenic mice reported here, in the MPS VII mice reported by Donsante et al (9), and in the patient with leukemia-like process after treatment of severe combined immunodeficiency with gene therapy (21,22). However, Donsante et al (9) concluded that the copy number of integrated rAAV cassettes was too low (far lower than one per diploid genome) to support the hypothesis that the tumors resulted from an integration event.…”

Section: Discussioncontrasting

confidence: 42%

“…Such was the case in the recently reported child with X-linked severe combined immunodeficiency who developed a leukemia-like process of T cells after treatment with gene-corrected autologous cells. In this patient, the retrovirus had inserted into a gene in which mutations are known to be involved in childhood cancers (21,22). It will be interesting to determine where the transgene inserted into the mouse DNA and to examine RNA from organs of both lines of overexpressing transgenic mice by microarray analysis to determine which, if any, other genes are up-regulated by each transgene.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transgene produces massive overexpression of human β-glucuronidase in mice, lysosomal storage of enzyme, and strain-dependent tumors

Vogler

Galvin²,

Levy³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

␤-Glucuronidase (GUSB) is a lysosomal enzyme important in the normal step-wise degradation of glycosaminoglycans. Deficiency of GUSB causes the lysosomal storage disease mucopolysaccharidosis VII (MPS VII, Sly disease). Affected patients have widespread progressive accumulation of ␤-glucuronide-containing glycosaminoglycans in lysosomes. Enzyme replacement, bone marrow transplantation, and gene therapy can correct lysosomal storage in the MPS VII mouse model. Gene therapy in MPS VII patients and animals may result in massive overexpression of GUSB in individual tissues, and the toxicity of such overexpression is incompletely investigated. To gain insight into the effect of massive overexpression of GUSB, we established 19 transgenic mouse lines, two of which expressed very high levels of human GUSB in many tissues. The founder overexpressing mice had from >100-to several thousand-fold increases in tissue and serum GUSB. The enzyme expression in most tissues decreased in subsequent generations in one line, and expression in liver and marrow fell in subsequent generations of the other. Both lines had morphologically similar widespread lysosomal storage of GUSB and secondary elevations of other lysosomal enzymes, a finding characteristic of lysosomal storage disease. One line developed tumors, and one did not. These transgenic models show that massive overexpression of a lysosomal enzyme can be associated with dramatic morphological alterations, which, at least in one of the two lines, had little clinical consequence. For the other transgenic line, the high frequency of tumor development in F2 FVB progeny suggests that the vector used to generate the transgenic lines has an integration site-dependent potential to be oncogenic, at least in this strain background.Sly disease ͉ MPS VII ͉ lysosomal storage disease ͉ gene therapy ͉ tumor susceptibility M ost patients with lysosomal storage disease (LSD) have a deficiency of a lysosomal enzyme important in the normal stepwise degradation of a complex macromolecule (1). LSD in both humans and animal models can be effectively treated if relatively low levels of the deficient enzyme are delivered to the affected tissues, as occurs in bone marrow transplantation or enzyme replacement therapy (2-4). Transgenic mice that overexpress therapeutic proteins have been used as a source of donor cells to treat models of LSD, and it has been suggested that overexpressing cells may be more effective than normal cells for correction of lysosomal storage (5, 6). Viral-mediated gene therapy has also been shown to be therapeutic for murine mucopolysaccharidosis (MPS) VII and other animal models of LSD (7). Such therapy can produce high levels of therapeutic enzyme in individual tissues (8). The toxicity of such overexpression of a lysosomal enzyme is incompletely investigated, although a recent report described tumors in multiple adult MPS VII mice receiving neonatal injection of the human ␤-glucuronidase (HGUSB, EC 3.2.1.31) gene in an adeno-associated virus (rAAV) vector (9).We establish...

show abstract

Section: Discussioncontrasting

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Transgene produces massive overexpression of human β-glucuronidase in mice, lysosomal storage of enzyme, and strain-dependent tumors

Vogler

Galvin²,

Levy³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…21 However, the emergence of GT as a fully fledged area of medicine has been slow and paved with disappointments and retraction of investment along the way. [22][23][24] In spite of the relatively few success stories and tragically the occurrence of some fatalities, the number of GT trials underway affirms that there is continued interest and belief in the promise of GT. 25 Interestingly, Glybera, a product that treats the single gene disease lipoprotein lipase deficiency (LPLD), was the first GT product approved by the European Commission in November 2012 making it the first GT product approved by the regulatory bodies in the Western world.…”

mentioning

confidence: 99%

Non-viral gene-activated matrices

et al. 2013

View full text Add to dashboard Cite

“…The gene delivery systems in vivo can be categorized as viral and non-viral approaches. 3,4) Safety in the usage of viral vectors for clinical gene therapy is not yet sufficient, 5,6) whereas naked plasmid DNA (pDNA), which is a typical non-viral vector, has advantages in safety compared with a viral vector. Recently, gene transfection efficiency using non-viral vectors has improved due to the development of various gene carriers such as cationic liposomes.…”

mentioning

confidence: 99%