Pharmacokinetic Study of Viral Vectors for Gene Therapy: Progress and Challenges

Xu, Xianxing; Jingwen, Yang; Cheng, Yiwei

doi:10.5772/21259

Cited by 3 publications

(10 citation statements)

References 48 publications

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“…Because each cell division contains the genetic material of the provirus integrated, ready to be replicated, transcribed, and translated alongside the DNA of the original cell, this mechanism has the potential to achieve lifelong expression of the therapeutic nucleic acid. This genomic integration has the potential to influence several aspects of retrovirus behavior, including their overall availability to cells of interest, the rate of unwanted accumulation in nontargeted tissues, and distal toxicity [13, 23]. In terms of the overall immunogenic profile of the system, as well as the stability and rate of degradation of ribonucleic acid in the final formulation, RNA-based delivery systems outperform.…”

Section: Key Findingsmentioning

confidence: 99%

“…Using rodent models, the researchers discovered that recombinant adeno-associated viral vectors of serotype 6 (rAAV6) accumulate primarily in the liver, but also in equal amounts in the spleen, although after extraction of the animal organs, a nonspecific distribution pattern was observed that followed traces of the vectors found in several other tissues. Since other similar types of the same family (e.g., serotype 1) are considered as alternative vectors that have not yet shown promising results in gene delivery, they have not been studied in detail with respect to pharmacokinetics [23, 25, 26].…”

Section: Key Findingsmentioning

confidence: 99%

“…Attachment of polyethylene glycol to viral capsid molecules is a technique that can be applied to any vector to successfully increase its blood circulation, meaning that regardless of the external morphology of the particles, an efficient degree of coverage has been created to avoid immune recognition and opsonization [13, 29]. Adenoviral vectors, modified vaccinia virus, and herpes simplex virus type 1 are examples of replication-deficient viral vectors that persist in vivo for a short time before being eliminated by the organism [23].…”

Section: Key Findingsmentioning

confidence: 99%

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On the in vivo kinetics of gene delivery vectors

Kontogiannis

Karalis

2022

Preprint

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Gene therapy is the most promising strategy for treating a number of diseases at their most fundamental, genetic level, and it has a wide range of promising clinical and emerging preclinical uses in both the clinic and the laboratory. Gene therapy systems are composed of three fundamental components, with the delivery platform being responsible for the protection and successful delivery of the incorporated therapeutic nucleic acid sequences. A successful delivery platform is critical in the achievement of a therapeutic outcome, and an effective delivery platform is essential in achieving this. A variety of different gene delivery platforms - vectors - are evaluated in this dissertation in terms of their nature, mechanism of action, potential applications, and safety. Of particular importance is the evaluation of their post-delivery pharmacokinetic and adverse drug-metabolite profiles. The different types of vectors, including viral, non-viral, and alternative vectors, are discussed separately in each chapter, while important issues related to the incorporation of these vectors into clinical practice are discussed as well, including the topics of vector development and manufacturing, as well as the current regulatory landscape and efforts to improve it, and finally their prospects for the immediate future.

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Section: Key Findingsmentioning

confidence: 99%

Section: Key Findingsmentioning

confidence: 99%

Section: Key Findingsmentioning

confidence: 99%

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On the in vivo kinetics of gene delivery vectors

Kontogiannis

Karalis

2022

Preprint

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“…In vivo imaging has great potential to contribute to the design and optimization of AAVs. The biodistribution of viral vectors has previously been evaluated by real-time PCR, Southern blotting of the transduced gene, western blotting, immunohistochemistry (IHC), and in vivo imaging of reporter proteins 12 . Many of these methods are invasive, relying on small quantities of tissue at a single site and/or time point 13 .…”

mentioning

confidence: 99%

“…1a). The dose for systemic administration of AAVs in mice is low;~10 [11][12] vector genomes (vg) are injected, corresponding to 0.2-2 pmol of AAVs. Cu-64 has a halflife of 12.7 h and is therefore well suited to the AAV half-life in blood 34 ; however, combining 64 CuCl 2 (MA,~20 μCi/pmol) and 2 pmol of AAVs yields~40 μCi of labeled AAVs when the labeling ratio of Cu-64 to AAVs is 1:1.…”

mentioning

confidence: 99%

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation

et al. 2020

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Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t 1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP. eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

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A Review of Analytical Methods for Adeno-Associated Virus Vectors’ Biodistribution and Shedding Studies

Zou

2024

JCLR

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Adeno-associated virus (AAV)-based gene therapy (GT) products can effectively deliver transgenes to replace lost or defective genes, providing hope for patients. However, there is limited research on analytical methods for pre-clinical and clinical studies which could impede their development success. During the development of AAV-based GT products, it is crucial to define the biodistribution and shedding profiles following treatment. In this review, we summarize PK studies for the AAV-based GT products approved so far by U.S. Food and Drug Administration and European Medicines Agency. We then comparatively review the analytical methods employed to evaluate AAV vectors’ biodistribution and shedding of approved GT products. We further make recommendations on choice of methodologies for future GT product development based on the study data and the currently available regulatory guidance.

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Pharmacokinetic Study of Viral Vectors for Gene Therapy: Progress and Challenges

Cited by 3 publications

References 48 publications

On the in vivo kinetics of gene delivery vectors

On the in vivo kinetics of gene delivery vectors

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation

A Review of Analytical Methods for Adeno-Associated Virus Vectors’ Biodistribution and Shedding Studies

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