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In recent years, the field of in vivo gene transfer with adeno-associated virus (AAV) vectors has seen an extraordinary expansion of applications and investments. Results emerging from clinical trials (1) and the recent market approval of a gene therapy drug for lipoprotein lipase deficiency (2) contributed to the hype around this vector system (3). Indeed, AAV vectors have several features that make them an ideal tool for gene transfer, for example, parental virions are replication deficient and non-pathogenic (4), and vectors can drive expression of a transgene for several years (5, 6) despite the fact that they do not integrate efficiently into the host genome. In recent years, a portfolio of natural AAV isolates (AAV serotypes) differing in tissue tropism has been developed as vectors. This toolbox has been further expanded with engineered AAV capsids developed to enhance efficiency and specificity of gene delivery, and to escape antibody neutralization (7). At the vector genome level, availability of potent promoter/enhancer sequences, codon-optimization of transgenes, and development of self-complementary AAV vectors (8) further enhanced efficacy of gene transfer. Finally, the availability of scalable processes to produce AAV vectors in GMP contributed significantly to the expansion of the field. As the AAV vector technology reached a more mature stage, it has become clear that a better understanding of the interactions of viral vectors with the host immune system is needed. In this Research Topic of Frontiers in Immunology, the editors present a collection of reviews and research articles discussing the two sides of immune responses triggered by in vivo gene transfer. These responses in fact can be desirable when they result in induction of tolerance to the therapeutic transgene (9), or when they are exploited for vaccine development, as discussed by Nieto and Salvetti in their review article (10). Conversely, immunogenicity of the viral capsid or the transgene product can be detrimental, as it may result in lack or loss of efficacy following vector-mediated gene transfer. Evidence for the critical role of tolerance induction in the achievement of sustained therapeutic efficacy following gene transfer comes from the work of Liao and colleagues, which provides evidence that glucocorticoid-induced TNF receptor (GITR) and its ligand GITR-L are of fundamental importance for the induction of immune regulatory responses in gene transfer and that lack of expression of GITR-L on antigen presenting cells results in impaired induction of regulatory T cells (Tregs) (11). Indeed, evidence of the key function of Tregs for successful in vivo gene therapy comes from several studies (12), and Liu and colleagues further demonstrate this concept in a model of plasmid gene transfer for hemophilia A, in which a combination of B cell depleting and Treg-enhancing drugs is used to successfully modulate transgene immunogenicity (13).
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32Cationic Lipid Formulations Alter the In Vivo Tropism of AAV2/9 Vector in Lung
Cationic Lipid Formulations Alter the In Vivo Tropism of AAV2/9 Vector in Lung
72Biochemical, Pathological, and Skeletal Improvement of Mucopolysaccharidosis VI After Gene Transfer to Liver but Not to Muscle
Biochemical, Pathological, and Skeletal Improvement of Mucopolysaccharidosis VI After Gene Transfer to Liver but Not to Muscle
Read more31Adeno-associated Virus-mediated, Mifepristone-regulated Transgene Expression in the Brain
Adeno-associated Virus-mediated, Mifepristone-regulated Transgene Expression in the Brain
510Self-complementary AAV Vectors; Advances and Applications
Self-complementary AAV Vectors; Advances and Applications
210Adeno-Associated Virus Vectors in Clinical Trials
Adeno-Associated Virus Vectors in Clinical Trials
I.11AAV vectors and the host immune system: a complicated relationship
I.11AAV vectors and the host immune system: a complicated relationship
97. Stability and Inactivation of AAV Serotype 1 Vectors
97. Stability and Inactivation of AAV Serotype 1 Vectors
89Adeno-Associated Virus (AAV) Vectors in the CNS
Adeno-associated virus (AAV) vectors exhibit a number of properties that have made this vector system an excellent choice for both CNS gene therapy and basic neurobiological investigations. In vivo, the preponderance of AAV vector transduction occurs in neurons where it is possible to obtain long-term, stable gene expression with very little accompanying toxicity. Promoter selection, however, significantly influences the pattern and longevity of neuronal transduction distinct from the tropism inherent to AAV vectors. AAV vectors have successfully manipulated CNS function using a wide variety of approaches including expression of foreign genes, expression of endogenous genes, expression of antisense RNA and expression of RNAi. With the discovery and characterization of different AAV serotypes, as well as the creation of novel chimeric serotypes, the potential patterns of in vivo vector transduction have been expanded substantially, offering alternatives to the more studied AAV 2 serotype. Furthermore, the development of specific AAV chimeras offers the potential to further refine targeting strategies. These different AAV serotypes also provide a solution to the immune silencing that proves to be a realistic likelihood given broad exposure of the human population to the AAV 2 serotype. These advantageous CNS properties of AAV vectors have fostered a wide range of clinically relevant applications including Parkinson's disease, lysosomal storage diseases, Canavan's disease, epilepsy, Huntington's disease and ALS. In many cases the proposed therapies have progressed to phase I/II clinical trials. Each individual application, however, presents a unique set of challenges that must be solved in order to attain clinically effective gene therapies.
Read more6An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo
An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo
115An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo
An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo
22Systemic Cancer Gene Therapy Using Adeno-associated Virus Type 1 Vector Expressing MDA-7/IL24
Systemic Cancer Gene Therapy Using Adeno-associated Virus Type 1 Vector Expressing MDA-7/IL24
7Recombinant Adeno-associated Virus Vectors Efficiently Transduce Foreign Gene Into Bovine Aortic Endothelial Cells: Comparison With Adenovirus Vectors
Recombinant Adeno-associated Virus Vectors Efficiently Transduce Foreign Gene Into Bovine Aortic Endothelial Cells: Comparison With Adenovirus Vectors
Read more225Immune Responses to Adeno-Associated Virus Vectors
One of the biggest challenges in optimizing viral vectors for gene therapy relates to the immune response of the host. Adeno-associated virus (AAV) vectors are associated with low immunogenicity and toxicity, resulting in vector persistence and long-term transgene expression. The inability of AAV vectors to efficiently transduce or activate antigen presenting cells (APCs) may account for their decreased immunogenicity. AAV mediated gene therapy however, leads to the development of antibodies against the vector capsid. Anti-AAV antibodies have neutralizing effects that decrease the efficiency of in vivo gene therapy and can prevent vector re-administration. Furthermore, recent studies have shown that AAV vectors can elicit both cellular and humoral immune responses against the transgene product. Both cell-mediated response and humoral response to the delivered gene depend on a number of variables; including the nature of the transgene, the promoter used, the route and site of administration, vector dose and host factors. The response of the host to the vector, in terms of antigen-specific immunity, will play a substantial role in clinical outcome. It is therefore important to understand both, why AAV vectors are able to escape immunity and the circumstances and mechanisms that lead to the induction of immune responses. This review will summarize innate and adaptive immune responses to AAV vectors, discuss possible mechanisms and outline strategies, such as capsid modifications, use of alternative serotypes, or immunosuppression, which have been used to circumvent them.
Read more877. Antigen-Specific Modulation of Capsid Immunogenicity with Tolerogenic Nanoparticles Results in Successful AAV Vector Readministration
77. Antigen-Specific Modulation of Capsid Immunogenicity with Tolerogenic Nanoparticles Results in Successful AAV Vector Readministration
Read more304. Gene Therapy of Malignant Brain Tumor by a Novel Double-Stranded Adeno-Associated Viral (AAV) Vector Carrying the Decorin Gene
304. Gene Therapy of Malignant Brain Tumor by a Novel Double-Stranded Adeno-Associated Viral (AAV) Vector Carrying the Decorin Gene
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