Foamy Virus Vectors for HIV Gene Therapy

Olszko, Miles E.; Trobridge, Grant D.

doi:10.3390/v5102585

Cited by 15 publications

(12 citation statements)

References 79 publications

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“… 105 FV vectors have been designed and pseudotyped to have a broad host range, large packaging capacity, and high transduction efficiency in human hematopoietic cells, and developed as an alternative to MLV vectors for gene therapy of hematological disorders, particularly AIDS. 106 Low-resolution profiling of FV ISs showed integration preferences similar to, though weaker than, those of MLV for CpG islands and TSSs, 107 , 108 confirmed by more recent analysis on human HSPCs after transplantation in immunodeficient mice. 109 A study analyzed 139 FV-derived vector insertion sites recovered ex vivo from human HSPCs after transplantation in NOD/SCID mice, which showed a weak preference for integration close to oncogenes.…”

Section: Main Textmentioning

confidence: 70%

Interactions between Retroviruses and the Host Cell Genome

Poletti

Mavilio

2018

Molecular Therapy - Methods & Clinical Development

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Replication-defective retroviral vectors have been used for more than 25 years as a tool for efficient and stable insertion of therapeutic transgenes in human cells. Patients suffering from severe genetic diseases have been successfully treated by transplantation of autologous hematopoietic stem-progenitor cells (HSPCs) transduced with retroviral vectors, and the first of this class of therapies, Strimvelis, has recently received market authorization in Europe. Some clinical trials, however, resulted in severe adverse events caused by vector-induced proto-oncogene activation, which showed that retroviral vectors may retain a genotoxic potential associated to proviral integration in the human genome. The adverse events sparked a renewed interest in the biology of retroviruses, which led in a few years to a remarkable understanding of the molecular mechanisms underlying retroviral integration site selection within mammalian genomes. This review summarizes the current knowledge on retrovirus-host interactions at the genomic level, and the peculiar mechanisms by which different retroviruses, and their related gene transfer vectors, integrate in, and interact with, the human genome. This knowledge provides the basis for the development of safer and more efficacious retroviral vectors for human gene therapy.

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Section: Main Textmentioning

confidence: 70%

Interactions between Retroviruses and the Host Cell Genome

Poletti

Mavilio

2018

Molecular Therapy - Methods & Clinical Development

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“…However, the field now has a much broader appreciation of how different types of retroviruses target potentially unsafe genomic features such as genes and enhancer regions. 243 In this vein, vectors based on α-retroviruses, 386 β-retroviruses, 387 or spumaviruses, 388 each of which targets genes and enhancers to lesser extents than lentiviruses and γ-retroviruses, respectively, might prove safer than MLV-based vectors. The identification of the mechanisms of integration targeting for the lentiviruses and γ-retroviruses has additionally opened up new approaches to vector design.…”

Section: Retroviral Integration As a Therapeutic Toolmentioning

confidence: 99%

Retroviral DNA Integration

2016

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The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications.

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“…A cassette, that carried three anti-HIV targets in the form of short hairpins (tat/rev at site I and site II and to human CCR5), was able to confer 4 log reductions in HIV replication assays [49]. FV vectors are particularly useful for anti-HIV gene therapy, since using Lenti-based vectors for RNAi delivery could be problematic since the anti-HIV sequences can jeopardize the vector packaging process [62]. Beyond therapeutic gene transfer targeting single gene disorders, FV vectors designed to deliver shRNA through PolIII promoters after HSC transfer and transplantation provided a significant long-term downregulation of target genes [63].…”

Section: Therapeutic Gene Transfer In Murine Preclinical Modelsmentioning

confidence: 99%

FV Vectors as Alternative Gene Vehicles for Gene Transfer in HSCs

Simantirakis

Tsironis

Vassilopoulos

2020

Viruses

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Hematopoietic Stem Cells (HSCs) are a unique population of cells, capable of reconstituting the blood system of an organism through orchestrated self-renewal and differentiation. They play a pivotal role in stem cell therapies, both autologous and allogeneic. In the field of gene and cell therapy, HSCs, genetically modified or otherwise, are used to alleviate or correct a genetic defect. In this concise review, we discuss the use of SFVpsc_huHSRV.13, formerly known as Prototype Foamy Viral (PFV or FV) vectors, as vehicles for gene delivery in HSCs. We present the properties of the FV vectors that make them ideal for HSC delivery vehicles, we review their record in HSC gene marking studies and their potential as therapeutic vectors for monogenic disorders in preclinical animal models. FVs are a safe and efficient tool for delivering genes in HSCs compared to other retroviral gene delivery systems. Novel technological advancements in their production and purification in closed systems, have allowed their production under cGMP compliant conditions. It may only be a matter of time before they find their way into the clinic.

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Foamy Virus Vectors for HIV Gene Therapy

Cited by 15 publications

References 79 publications

Interactions between Retroviruses and the Host Cell Genome

Interactions between Retroviruses and the Host Cell Genome

Retroviral DNA Integration

FV Vectors as Alternative Gene Vehicles for Gene Transfer in HSCs

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