Treatment of human disease by adeno-associated viral gene transfer

Abstract

During the past decade, in vivo administration of viral gene transfer vectors for treatment of numerous human diseases has been brought from bench to bedside in the form of clinical trials, mostly aimed at establishing the safety of the protocol. In preclinical studies in animal models of human disease, adeno-associated viral (AAV) vectors have emerged as a favored gene transfer system for this approach. These vectors are derived from a replication-deficient, non-pathogenic parvovirus with a single-stranded DNA genome. Efficient gene transfer to numerous target cells and tissues has been described. AAV is particularly efficient in transduction of non-dividing cells, and the vector genome persists predominantly in episomal forms. Substantial correction, and in some instances complete cure, of genetic disease has been obtained in animal models of hemophilia, lysosomal storage disorders, retinal diseases, disorders of the central nervous system, and other diseases. Therapeutic expression often lasted for months to years. Treatments of genetic disorders, cancer, and other acquired diseases are summarized in this review. Vector development, results in animals, early clinical experience, as well as potential hurdles and challenges are discussed.

GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

“…38,39 Intriguingly, AAV vector genome realized liver transduction and subsequent released into the circulation, which is the most likely mechanism. This study demonstrates successful in vivo transduction via AAV2 vector which facilitated sustained GDF11 overexpression and obtained similar results on antiatherosclerotic effect compared with repeated intraperitoneal injection of recombinant GDF11, strongly suggesting that AAV represents a potential alternative to recombinant protein injection.…”

Rapid, Simple, and Versatile Manufacturing of Recombinant Adeno-Associated Viral Vectors at Scale

“…T he use of recombinant adeno-associated viral (rAAV) vectors for clinical gene therapy applications has become widespread and is largely due to the demonstration of longterm transgene expression from rAAV vectors in animal models with little associated toxicity and good overall safety profiles in both preclinical and clinical trials Moss et al, 2004;Warrington and Herzog, 2006;Maguire et al, 2008;Mueller and Flotte, 2008;Brantly et al, 2009). Most early AAV gene therapy studies were performed with serotype 2 vectors, but vector systems based on other AAV serotypes with more efficient gene delivery and different tissue specificity are currently in human trials and their use will likely increase (Brantly et al, 2009;Neinhuis, 2009).…”

Augmented transgene expression in transformed cells using a parvoviral hybrid vector

“…[31][32][33]81 The aim of this study was to test the properties of a hybrid vector consisting of the p4-ns1-p38 expression cassette derived from the autonomous parvovirus H1 incorporated into the AAV capsid, thanks to its flanking with AAV ITRs. Gene expression using this cassette has been shown to be enhanced in transformed cells compared to non-transformed cells, thereby providing a generally increased transgene expression in various transformed and tumor cells.…”

“…31 This included their application in cancer gene therapy by delivering tumor suppressor genes, cytotoxic genes, drug resistance genes and genes coding for immunomodulators or antiangiogenesis factors. [31][32][33] In this study, we constructed a hybrid vector by introducing the autonomous parvovirus H1-derived expression cassette consisting of the p4 promoter, the NS1 gene and the p38 promoter into AAV capsids and analyzed the transduction properties of this vector in comparison to AAV2 vectors expressing transgenes under the control of the homologous AAV p5-rep-p40 expression cassette or a standard cytomegalovirus (CMV) promoter. The hybrid vector showed a superior transduction activity compared to other AAV2 vectors in HeLa cells and could become further stimulated by adenovirus, irradiation or cytotoxic agents.…”