Tag: <span>adeno-associated viral vectors</span>

Defining Therapeutic Window for Viral Vectors: A Statistical Framework to Improve Consistency in Assigning Product Dose Values

NOTE: Page 7 of this article has been revised to correct an error in the original article which stated that “..the probability of failing a lot when it actually is not equivalent, becomes 1-2*α.” The correct equation, 1-α, has replaced the errant one and a single sentence following it was added to further clarify this concept.

ABSTRACT: Pre-clinical and clinical trials conducted to establish the minimum effective dose and the maximum tolerated dose of a viral vector assume that the assigned dose values are comparable across studies. Toxicity has been associated with high dose administration of both adenovirus and adeno-associated virus-based vectors, and increased attention must be paid to assays used to measure dose. High assay variability can be mitigated by replication and the reporting of a mean value for product lot release. The establishment of a dose specification and a testing strategy must take into account the risk of errant quality control decisions. This can be accomplished by linking assay qualification information to measurement uncertainty through a statistical framework. By adopting an equivalence approach, the risk of releasing lots with unacceptably high or low dose values is minimized by reducing measurement uncertainty. This article provides a worked-through example to introduce applicable statistical concepts and the equations necessary to facilitate their implementation in the field.

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Risk Analysis and Management Viral Vectors

adeno-associated viral vectors adenoviral vectors assay qualification dosage dose-determining assay equivalence limits therapeutic window

Manufacture and Stability of the Recombinant Adeno-Associated Virus Serotype 2 Vector Reference Standard

Recombinant adeno-­associated viral (rAAV) vectors have proven to be efficient vehicles for gene transfer in animal models. The attractive features of this vector system are long-term gene expression with little or no associated toxicities following administration to a variety of tissues. Previous and ongoing clinical trials in humans demonstrate a very good over-all safety profile. However, one of the caveats of this work that has been carried out by several ­laboratories is the inability to normalize vector doses administered by different investigators to animals and humans. Most of the work to date has involved AAV serotype2 vectors, but vector systems based on other AAV ­serotypes are being rapidly developed…

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Viral Reference Materials Viral Vectors

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Viral Gene Vectors

An astonishing range of viruses has provided building blocks for gene delivery systems, from the simple adeno-associated virus with a 5 kb genome to the complex poxviruses with 300 kb. This review focuses on non-replicating viral vectors that infect host cells just once, without producing infections virus. Viral vectors are generally characterized by several criteria, including their ability to integrate into the host genome, coding capacity, titer, toxicity, immunogenicity, host range, duration of gene expression, and transient or stable production systems. These are precisely the features that need to be carefully studied in the context of the application when deciding which vector to use…

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Biologics Production Cell & Gene Therapy Viral Vectors

adeno-associated viral vectors adenoviral vectors gene delivery gene therapy non-replicating viral vectors vaccines

Utility of a Recombinant Adeno-Associated Viral Vector Reference Standard

Recombinant adeno-associated viral (rAAV) vectors are known to be efficient vehicles for gene transfer in animal models. The attractive feature of this vector system consists primarily of long-term gene expression with little or no associated toxicities following administration to a variety of tissues. Previous and ongoing clinical trials in humans demonstrate a very good overall safety profile, but problems persist due to the lack of any systematic method for normalizing doses administered to animals and humans. To date, most of the work involves AAV serotype 2 vectors, but vector systems based on other AAV serotypes continue to develop rapidly. Administered doses are usually based on titer, but the defective nature of AAV makes determining vector infectious units difficult. Titering methods based on vector genomes (using hybridization, real-time PCR, or spectrophotometry) are more reliable, but give no information as to the infectivity of the vector. Determining infectious titer is critical, as the ratio of infectious virions to vector genome-containing virions helps to determine the dose, potency, and strength of the vector preparation…

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Viral Reference Materials Viral Vectors

adeno-associated viral vectors infectious titer recombinant proteins safety standards