Systemic Delivery of a High-Capacity Adenoviral Vector Expressing Mouse CTLA4Ig Improves Skeletal Muscle Gene Therapy

Jiang, Zhilong; Feingold, Eleanor; Kochanek, Stefan; Clemens, Paula R.

doi:10.1006/mthe.2002.0676

Cited by 24 publications

(15 citation statements)

References 26 publications

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“…This method was tested using two genes that block costimulatory signals that are required for an optimal immune response. 61,62 These authors report that the immunomodulatory genes CTLA4Ig and CD40Ig included in one HD vector and coadministered with an Ad vector coding for a reporter gene resulted in higher levels of transgene expression, lower levels of anti-Ad antibody and more prolonged transgene expression, when compared to controls. However, prolonged expression of these immunomodulatory genes compromised the host immune response.…”

Section: Readministration With Ad Vectors Remains a Challengementioning

confidence: 99%

Gene therapy progress and prospects: adenoviral vectors

George¹

2003

Gene Ther

264

165

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In September 1999, the perceptions of the use of adenoviral (Ad) vectors for gene therapy were altered when a patient exposed via the hepatic artery to a high dose of adenoviral vector succumbed to the toxicity related to vector administration. Appropriately, concerns were raised about continued use of the Ad vector system and, importantly, there were increased efforts to more fully understand the toxicity. Today it is recognized that there is no ideal vector system, and that while Ad vectors are not suitable for all applications, the significant advantages over other vector systems including efficient transduction of a variety of cell types, both quiescent and dividing, make it optimal for certain applications. These include protocols where high levels of short-term expression are sufficient to provide a therapeutic benefit. Potential target applications include therapeutic angiogenesis, administration into immune-privileged sites such as the CNS, or treatments where the adjuvant effect of adenovirus can be of benefit such as cancer vaccines. Broader applicability of Ad vectors will require resolution of toxicity issues. This review will therefore focus on studies conducted over the last 2 years that have advanced our understanding of the toxicity associated with Ad vectors, studies that have employed methods to reduce toxicity and improvements in Ad vectors themselves that will reduce toxicity by one of several mechanisms. These mechanisms include retargeting vector to the tissue of interest, minimizing or eliminating viral gene expression that is thought to result in loss of transduced cells, or by methods that seek to reduce the vector dose required for therapeutic benefit. An area where there remains significant room for improvement is when readministration of vector is required because transgene expression has decreased to background levels.

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Section: Readministration With Ad Vectors Remains a Challengementioning

confidence: 99%

Gene therapy progress and prospects: adenoviral vectors

George¹

2003

Gene Ther

264

165

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“…Jiang and colleagues demonstrate that systemic delivery of cytotoxic T lymphocyte associated protein 4 and the Fc portion of immunoglobulin G (IgG) in adenoviral vectors, reduces the level of neutalising antibodies to AdV and enhanced Green Fluorescent Protein [67]. In these experiments sustained and stable transgene expression was noted for at least 2 months in muscle and expression was significantly higher than in controls.…”

Section: Immunosuppressionmentioning

confidence: 91%

Therapeutic DNA Delivery to Skeletal Muscle

Quigley¹,

Lowes²,

Kornberg³

et al. 2006

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Gene therapy has advanced rapidly over the last few decades due to the development of viral and plasmid vectors for gene delivery and strategies for the direct alteration of DNA/RNA species. Gene replacement using modified viral vectors and plasmids has yielded the greatest levels of therapeutic protein expression in muscle to date, however there are issues with immune mediated response to transgene and viral proteins, hindering sustained expression. New efforts have been made to make viral delivery of genes safer and sustainable, these include the development of hybrid vectors and "gutted" helper dependant vectors.Non-viral methods of gene delivery and repair provide an alternative to viral based methods. Major concerns with nonviral approaches include the effective distribution and integration of therapeutic molecules throughout the muscle. However, a number of methods have been developed to overcome these obstacles. These include electroporation, vascular injection and occlusion, myotoxins promoting muscle regeneration, muscle specific promoters and the use of pharmacological agents to enhance DNA delivery for gene delivery or gene repair. A number of non-viral plasmid based protocols for gene delivery to muscle have reached the clinical trial stage and show great promise. This review discusses recent advances in viral and non-viral based therapies for muscle diseases, the issues faced by these technologies and current efforts to overcome these obstacles.

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“…Finally, blocking co-stimulatory pathways can be used to modulate the host adaptive immune response. Several groups showed that an antibody against CD40 ligand (Scaria et al, 1997;Wilson et al, 1998) or expressing CTLA4Ig, a fusion protein of cytotoxic T lymphocyteassociated protein 4 (CTLA4) and the Fc portion of immunoglobulin G (IgG), by the HD-Ad vector, improved transgene expression in rodents (Jiang et al, 2002;Yamashita et al, 2003).…”

Section: Adaptive Immune Responsementioning

confidence: 99%

Gene therapy: light is finally in the tunnel

Cao

Molday

2011

Protein Cell

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After two decades of ups and downs, gene therapy has recently achieved a milestone in treating patients with Leber's congenital amaurosis (LCA). LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy. Mutations in several genes, including RPE65, cause the disease. Using adeno-associated virus as a vector, three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects. However, considering the whole field of gene therapy, there are still major obstacles to clinical applications for other diseases. These obstacles include innate and immune barriers to vector delivery, toxicity of vectors and the lack of sustained therapeutic gene expression. Therefore, new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy. In this article, we shall review the major advancements over the past two decades and, using lung gene therapy as an example, discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research.

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Systemic Delivery of a High-Capacity Adenoviral Vector Expressing Mouse CTLA4Ig Improves Skeletal Muscle Gene Therapy

Cited by 24 publications

References 26 publications

Gene therapy progress and prospects: adenoviral vectors

Gene therapy progress and prospects: adenoviral vectors

Therapeutic DNA Delivery to Skeletal Muscle

Gene therapy: light is finally in the tunnel

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