Progress and Prospects: Gene Therapy Clinical Trials (Part 2)

Griesenbach, Uta

doi:10.1038/sj.gt.3303033

Cited by 65 publications

(9 citation statements)

References 45 publications

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“…Gene therapy can potentially treat inherited diseases 1,2 as well as acquired diseases such as cancers 3 , cardiovascular diseases 1 , intraocular diseases 1 and viral infections 4,5 . However, this revolutionary method has yet to deliver on its promise due in large part to the lack of safe and efficient means of delivering therapeutic genes 6 .…”

Section: Introductionmentioning

confidence: 99%

Design of Hybrid Lipid/Retroviral-Like Particle Gene Delivery Vectors

2013

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Recombinant retroviruses provide highly efficient gene delivery and the potential for stable gene expression. The retroviral envelope protein, however, is the source of significant disadvantages such as immunogenicity, poor stability (half-life of transduction activity of 5-7 h at 37 °C for amphotropic murine leukemia virus) and difficult production and purification. To address these problems, we report construction of efficient hybrid vectors through association of murine leukemia virus (MLV)-like particles (M-VLP) with synthetic liposomes comprising DOTAP, DOPE and cholesterol (φ/M-VLP). We conclude that the lipid composition is a significant determinant of the transfection efficiency and uptake of φ/M-VLP in HEK293 cells with favorable compositions for transfections being those with low DOTAP, low DOPE and high cholesterol content. Cellular uptake, however, was dependent on DOTAP content alone. By extrusion of liposomes prior to vector assembly, the size of these hybrid vectors could also be decreased to ≈300 nm, as confirmed via DLS and TEM. φ/M-VLP were also robust on storage in terms of vector size and transfection efficiency and provided stable transgene expression over a period of three weeks. We conclude that the non-covalent combination of biocompatible synthetic lipids with inactive retroviral particles to form a highly efficient hybrid vector is a significant extension to the development of novel gene delivery platforms.

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Section: Introductionmentioning

confidence: 99%

Design of Hybrid Lipid/Retroviral-Like Particle Gene Delivery Vectors

2013

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“…Several factors may influence the development of an immune response to AAV 19 , including vector serotypes, route of administration, vector doses, host species, the presence of preexisting immunity, and the specifications of the delivery cassette. In mice 20 and non-human primates 21 , the AAV2 serotype elicits a stronger immune response than the AAV7 or AAV8 serotypes. With respect to route of administration, systemic delivery of AAV vectors often results in immune tolerance and is less likely to induce an immune reaction to the transgene than intramuscular delivery 22,23 .…”

Section: Introductionmentioning

confidence: 99%

Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver

et al. 2010

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Vectors based on adeno-associated virus (AAV) are effective in gene delivery in vivo. Tissue-specific gene expression is often needed to minimize ectopic expression in unintended cells and undesirable consequences. Here we investigated if incorporation of target sequences of tissue-specific microRNA (miRNA) into AAV vectors could inhibit ectopic expression in tissues such as the liver and hematopoietic cells. First we inserted liver-specific miR-122 target sequences (miR-122T) into the 3′ untranslated region (UTR) of a number of AAV vectors. After intravenous delivery in mice, we found that 5 copies of the 20mer miR-122T reduced liver expression of luciferase by 50-fold and β-galactosidase (LacZ) by 70-fold. Five copies of miR-122T also reduced mRNA levels of a secretable protein (myostatin propeptide) from the AAV vector plasmid by 23–fold in the liver. However, gene expression in other tissues including the heart was not inhibited. Similarly, we inserted 4 copies of miR-142-3pT or miR-142-5pT, both hematopoietic lineage-specific, into the 3′ UTR of the AAV-luciferase vector. We wished to see if they could prolong transgene expression by inhibiting expression in antigen-presenting cells. However, in vivo luciferase gene expression in major tissues declined with time regardless of the miR-142 target sequences used. Quantitative analysis of the vector DNA in various tissues revealed that the decline of transgene expression in vivo was mainly due to promoter shut-off other than loss of AAV-transduced cells by immune destruction. Moreover, transgene expression was not detected in circulating mononuclear cells after delivering AAV9 vector with or without miR142T. These results demonstrate that live-specific miR-122 target sequence in AAV vectors was highly efficient in reducing liver expression, whereas hematopoietic miR-142 target sequences were ineffective in preventing decline of AAV vector gene expression in non-hematopoietic tissues resulted from promoter shut-off.

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“…Harnessing the explosion in biological knowledge will see a world reshaped by robotics, 2 nanotechnology, 3,4 genetic engineering, 5 stem cell research 6,7 and tissue engineering 8 . The line separating humans from machines will blur and integrating artificial materials with tissues will become commonplace.…”

Section: Introductionmentioning

confidence: 99%

Tissue Compatibility of Biomaterials: Benefits and Problems of Skin Biointegration

Stynes

Kiroff

Morrison

et al. 2008

ANZ Journal of Surgery

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The integration of biomaterials with skin is necessary to enable infection-free access to vasculature and body cavities. Also, integrating plastics and metals with skin increases options for the reconstruction of surgical and traumatic defects and enables the permanent implantation of robotic and electronic devices. Until now, attempts to integrate biomaterials with skin permanently have failed because of epidermal marsupialization and infection. This article reviews the general properties required of biomaterials to optimize integration with body tissues, the modifications that increase biocompatibility, focusing particularly on surface functionalization and the specific requirements for biomaterial integration into skin. Critical pathophysiological processes relating to biocompatibility are discussed with particular emphasis on the skin-biomaterial interface. Future directions are speculated on, in particular, the specific utility of subatmospheric pressure dressings in facilitating tissue integration into biomaterials.

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Progress and Prospects: Gene Therapy Clinical Trials (Part 2)

Cited by 65 publications

References 45 publications

Design of Hybrid Lipid/Retroviral-Like Particle Gene Delivery Vectors

Design of Hybrid Lipid/Retroviral-Like Particle Gene Delivery Vectors

Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver

Tissue Compatibility of Biomaterials: Benefits and Problems of Skin Biointegration

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