The host range of retroviral vectors including lentiviral vectors can be expanded or altered by a process known as pseudotyping Pseudotyped lentiviral vectors consist of vector particles bearing glycoproteins (GPs) derived from other enveloped viruses Such particles possess the tropism of the virus from which the GP was derived For example, to exploit the natural neural tropism of rabies virus, vectors designed to target the central nervous system have been pseudotyped using rabies virus-derived GPs Among the first and still most widely used GPs for pseudotyping lentiviral vectors is the vesicular stomatitis virus GP (VSV-G), due to the very broad tropism and stability of the resulting pseudotypes Pseudotypes involving VSV-G have become effectively the standard for evaluating the efficiency of other pseudotypes This review samples a few of the more prominent examples from the ever-expanding list of published lentiviral pseudotypes, noting comparisons made with pseudotypes involving VSV-G in terms of titer, viral particle stability, toxicity, and host-cell specificity Particular attention is paid to publications of successfully targeting a specific organ or cell types

Altering the tropism of lentiviral vectors through pseudotyping.

We report findings from a clinical evaluation of lentiviral vectors in a phase I open-label nonrandomized clinical trial for HIV. This trial evaluated the safety of a conditionally replicating HIV-1-derived vector expressing an antisense gene against the HIV envelope. Five subjects with chronic HIV infection who had failed to respond to at least two antiviral regimens were enrolled. A single i.v. infusion of gene-modified autologous CD4 T cells was well tolerated in all patients. Viral loads were stable, and one subject exhibited a sustained decrease in viral load. CD4 counts remained steady or increased in four subjects, and sustained gene transfer was observed. Self-limiting mobilization of the vector was observed in four of five patients. There is no evidence for insertional mutagenesis after 21–36 months of observation. Immune function improved in four subjects. Lentiviral vectors appear promising for gene transfer to humans.

/pdf/gene-transfer-in-humans-using-a-conditionally-replicating-48k5jg0gc1.pdf

Gene transfer in humans using a conditionally replicating lentiviral vector

The capacity to efficiently transduce nondividing cells, shuttle large genetic payloads, and maintain stable long-term transgene expression are attributes that have brought lentiviral vectors to the forefront of gene delivery vehicles for research and therapeutic applications in a clinical setting. Our discussion initiates with advances in lentiviral vector development and how these sophisticated lentiviral vectors reflect improvements in safety, regarding the prevention of replication competent lentiviruses (RCLs), vector mobilization, and insertional mutagenesis. Additionally, we describe conventional molecular regulatory systems to manage gene expression levels in a spatial and temporal fashion in the context of a lentiviral vector. State of the art technology for lentiviral vector production by transient transfection and packaging cell lines are explicitly presented with current practices used for concentration, purification, titering, and determining the safety of a vector stock. We summarize lentiviral vector applications that have received a great deal of attention in recent years including the generation of transgenic animals and the stable delivery of RNA interference molecules. Concluding remarks address some of the successes in preclinical animals, and the recent transition of lentiviral vectors to human clinical trials as therapy for a variety of infectious and genetic diseases.

Gene delivery by lentivirus vectors

Replication defective vectors derived from simple retroviruses or the more complex genomes of lentiviruses continue to offer the advantages of long-term expression, cell and tissue specific tropism, and large packaging capacity for the delivery of therapeutic genes. The occurrence of adverse events caused by insertional mutagenesis in three patients in a gene therapy trial for X-linked SCID emphasizes the potential for problems in translating this approach to the clinic. Several genome-wide studies of retroviral integration are now providing novel insights into the integration site preferences of different vector classes. We review recent developments in vector design, integration, biosafety, and production.

Gene Therapy Progress and Prospects: Development of improved lentiviral and retroviral vectors – design, biosafety, and production

More than two decades have passed since genetically modified HIV was used for gene delivery. Through continuous improvements these early marker gene-carrying HIVs have evolved into safer and more effective lentiviral vectors. Lentiviral vectors offer several attractive properties as gene-delivery vehicles, including: (i) sustained gene delivery through stable vector integration into host genome; (ii) the capability of infecting both dividing and non-dividing cells; (iii) broad tissue tropisms, including important gene- and cell-therapy-target cell types; (iv) no expression of viral proteins after vector transduction; (v) the ability to deliver complex genetic elements, such as polycistronic or intron-containing sequences; (vi) potentially safer integration site profile; and (vii) a relatively easy system for vector manipulation and production. Accordingly, lentivector technologies now have widespread use in basic biology and translational studies for stable transgene overexpression, persistent gene silencing, immunization, in vivo imaging, generating transgenic animals, induction of pluripotent cells, stem cell modification and lineage tracking, or site-directed gene editing. Moreover, in the present high-throughput '-omics' era, the commercial availability of premade lentiviral vectors, which are engineered to express or silence genome-wide genes, accelerates the rapid expansion of this vector technology. In the present review, we assess the advances in lentiviral vector technology, including basic lentivirology, vector designs for improved efficiency and biosafety, protocols for vector production and infection, targeted gene delivery, advanced lentiviral applications and issues associated with the vector system.

Lentiviral vectors: basic to translational

This review is intended to exemplify the roles and responsibilities of the two agencies under the Department of Health and Human Services, the National Institutes of Health and the Food and Drug Administration, that have oversight for human gene transfer clinical protocols, as seen through our experience of bringing a first-in-its-class lentiviral vector to clinical trials. In response to the changing circumstances in gene therapy research between 1999 and 2002, the concerns of these agencies regarding gene therapy have been evolving. This review provides an overview of the major safety concerns regarding insertional oncogenesis, the generation of a replication- competent lentivirus (RCL), and vector mobilization thought to be related to lentiviral vectors, which had to be addressed during the regulatory review process before initiating the clinical trial. Specific monitoring assays to address these concerns were established to test for RCL generation, vector mobilization, persistence of vector-modified cells, and abnormal clonal expansion of modified cells. We hope to provide a basic understanding and appreciation of the regulatory process and major safety concerns, toward providing useful insight to those presently embarking on the development of clinical application of lentiviral vectors.

Regulatory considerations for novel gene therapy products: a review of the process leading to the first clinical lentiviral vector.

QC Release Testing of an HIV-1 Based Lentiviral Vector Lot and Transduced Cellular Product

The present invention provides improved conditionally replicating vectors that have improved safety against the generation of replication competent vectors or virus. Also disclosed are methods of making, propagating and selectively packaging, modifying, and using such vectors. Included are improved helper constructs, host cells, for use with the improved vectors as well as pharmaceutical compositions and host cells comprising the vectors, the use of vector containing host cells to screen drugs, and methods of using the vectors to determine gene function. The methods also include the prophylactic and therapeutic treatment of disease, especially viral infection, and HIV infection in particular.

Conditionally replicating vectors for inhibiting viral infections

The present invention provides improved conditionally replicating vectors that have improved safety against the generation of replication competent vectors or virus. Also disclosed are methods of making, propagating and selectively packaging, modifying and using vectors. Included are improved helper constructs, host cells, for use with the improved vectors as well as pharmaceutical compositions and host cells comprising the vectors, the use of vector containing host cells to screen drugs, and methods of using the vectors to determine gene function. The methods also include the prophylactic and therapeutic treatment of disease, especially viral infection, and HIV infection in particular.

Improved conditionally replicating vectors for inhibiting viral infections

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Regulatory considerations for novel gene therapy products: a review of the process leading to the first clinical lentiviral vector.

QC Release Testing of an HIV-1 Based Lentiviral Vector Lot and Transduced Cellular Product

Conditionally replicating vectors for inhibiting viral infections

Improved conditionally replicating vectors for inhibiting viral infections