Use of nonviral promoters in adenovirus‐mediated gene therapy: reduction of lysosomal storage in the aspartylglucosaminuria mouse

Virta, Salli; Rapola, Juhani; Jalanko, Anu; Lainé, Muriel

doi:10.1002/jgm.892

Cited by 23 publications

(14 citation statements)

References 31 publications

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“…Already in the 1990’s, bone marrow transplantation (BMT) was carried out with some patients, but the therapeutic effect remained very benign as compared to the side effects of BMT2324. In addition, the two existing AGU mouse models2526 have been subjected to therapy trials using ERT or gene therapy10111213, but these studies have so far not led to clinical trials with patients, despite their beneficial effects. ERT as a potential AGU therapy has been hampered by difficulties to produce sufficient amounts of recombinant AGA enzyme for therapy of human patients.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Banning

Gülec

Rouvinen

et al. 2016

Sci Rep

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Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU.

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Section: Discussionmentioning

confidence: 99%

“…Currently, no treatment for AGU is available, although several preclinical studies aiming at enzyme replacement (ERT)1011 or gene therapy1213 have been published. Neither of these treatment options is expected to be available within the next few years, and there is thus a vast demand for an alternative therapy for AGU.…”

mentioning

confidence: 99%

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Banning

Gülec

Rouvinen

et al. 2016

Sci Rep

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“…Since transgenes are encoded in adenoviral vectors as DNA, selective expression can be achieved by using cell-specific promoters. Reported examples include the catecholaminergic selective promoter PRS (Howorth et al, 2009), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), and lysosomal aspartylglucosaminidase (AGA) (Virta et al, 2006) and others.…”

Section: Introductionmentioning

confidence: 99%

Viral strategies for studying the brain, including a replication‐restricted self‐amplifying delta‐G vesicular stomatis virus that rapidly expresses transgenes in brain and can generate a multicolor golgi‐like expression

Pol

Özduman

Wollmann

et al. 2009

J of Comparative Neurology

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Viruses have substantial value as vehicles for transporting transgenes into neurons. Each virus has its own set of attributes for addressing neuroscience-related questions. Here we review some of the advantages and limitations of herpes, pseudorabies, rabies, adeno-associated, lentivirus, and others to study the brain. We then explore a novel recombinant vesicular stomatitis virus (dG-VSV) with the G-gene deleted and transgenes engineered into the first position of the RNA genome, which replicates only in the first brain cell infected, as corroborated with ultrastructural analysis, eliminating spread of virus. Because of its ability to replicate rapidly and to express multiple mRNA copies and additional templates for more copies, reporter gene expression is amplified substantially, over 500-fold in 6 hours, allowing detailed imaging of dendrites, dendritic spines, axons, and axon terminal fields within a few hours to a few days after inoculation. Green fluorescent protein (GFP) expression is first detected within 1 hour of inoculation. The virus generates a Golgilike appearance in all neurons or glia of regions of the brain tested. Whole-cell patch-clamp electrophysiology, calcium digital imaging with fura-2, and time-lapse digital imaging showed that neurons appeared physiologically normal after expressing viral transgenes. The virus has a wide range of species applicability, including mouse, rat, hamster, human, and Drosophila cells. By using dG-VSV, we show efferent projections from the suprachiasmatic nucleus terminating in the periventricular region immediately dorsal to the nucleus. DG-VSVs with genes coding for different color reporters allow multicolor visualization of neurons wherever applied. J. Comp. Neurol. 516:456-481, 2009.

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“…These include CMV, NSE, platelet-derived growth factor-b and CMV-chicken β-actin (Shevtsova et al 2005). Similar studies have been performed using Ad and lentiviral vectors (Jakobsson et al 2003; Virta et al 2006). Cell specificity achieved by particular promoters can vary between different CNS regions (Peel et al 1997).…”

Section: Targeted Gene Transfer and Regulatable Expressionmentioning

confidence: 53%

Using viral vectors as gene transfer tools (Cell Biology and Toxicology Special Issue: ETCS-UK 1 day meeting on genetic manipulation of cells)

2009

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In recent years, the development of powerful viral gene transfer techniques has greatly facilitated the study of gene function. This review summarises some of the viral delivery systems routinely used to mediate gene transfer into cell lines, primary cell cultures and in whole animal models. The systems described were originally discussed at a 1-day European Tissue Culture Society (ETCS-UK) workshop that was held at University College London on 1st April 2009. Recombinant-deficient viral vectors (viruses that are no longer able to replicate) are used to transduce dividing and post-mitotic cells, and they have been optimised to mediate regulatable, powerful, long-term and cell-specific expression. Hence, viral systems have become very widely used, especially in the field of neurobiology. This review introduces the main categories of viral vectors, focusing on their initial development and highlighting modifications and improvements made since their introduction. In particular, the use of specific promoters to restrict expression, translational enhancers and regulatory elements to boost expression from a single virion and the development of regulatable systems is described.

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Use of nonviral promoters in adenovirus‐mediated gene therapy: reduction of lysosomal storage in the aspartylglucosaminuria mouse

Abstract: These data implicate that tissue-specific promoters are especially useful in virus-mediated gene therapy aiming at long-term gene expression.

Cited by 23 publications

References 31 publications

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Viral strategies for studying the brain, including a replication‐restricted self‐amplifying delta‐G vesicular stomatis virus that rapidly expresses transgenes in brain and can generate a multicolor golgi‐like expression

Using viral vectors as gene transfer tools (Cell Biology and Toxicology Special Issue: ETCS-UK 1 day meeting on genetic manipulation of cells)

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