Journal ArticleDOI
Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors.
Sylvie Boutin,Virginie Monteilhet,Philippe Veron,Christian Leborgne,Olivier Benveniste,Marie Montus,Carole Masurier +6 more
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TLDR
Characterization of the preexisting humoral responses to the AAV capsid and cross-reactivity will allow development of new strategies to circumvent AAV acquired immune responses, and vectors based on AAV5, AAV8, and AAV9 may have an advantage for gene therapy in humans.Abstract:
Adeno-associated viruses (AAVs) are small, nonenveloped single-stranded DNA viruses that require helper viruses to facilitate efficient replication. Despite the presence of humoral responses to the wild-type AAV in humans, AAV remains one of the most promising candidates for therapeutic gene transfer to treat many genetic and acquired diseases. Characterization of the IgG subclass responses to AAV and study of the prevalence of both IgG and neutralizing factors to AAV types 1, 2, 5, 6, 8, and 9 in the human population are of importance for the development of new strategies to overcome these immune responses. Natural exposure to AAV types 1, 2, 5, 6, 8, and 9 can result in the production of antibodies from all four IgG subclasses, with a predominant IgG1 response and low IgG2, IgG3, and IgG4 responses. Prevalences of anti-AAV1 and -AAV2 total IgG determined by enzyme-linked immunosorbent assay were higher (67 and 72%) than those of anti-AAV5 (40%), anti-AAV6 (46%), anti-AAV8 (38%), and anti-AAV9 (47%). Furthermore, data showed that cross-reactions are important. The two highest neutralizing factor seroprevalences were observed for AAV2 (59%) and AAV1 (50.5%) and the lowest were observed for AAV8 (19%) and AAV5 (3.2%). Vectors based on AAV5, AAV8, and AAV9 may have an advantage for gene therapy in humans. Furthermore, among individuals seropositive for AAV5, AAV8, and AAV9, about 70-100% present low titers. Better characterization of the preexisting humoral responses to the AAV capsid and cross-reactivity will allow development of new strategies to circumvent AAV acquired immune responses.read more
Citations
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Journal ArticleDOI
Adeno-associated virus vector as a platform for gene therapy delivery
TL;DR: The fundamentals of AAV and vectorology are discussed, focusing on current therapeutic strategies, clinical progress and ongoing challenges.
Journal ArticleDOI
Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain
Benjamin E. Deverman,Piers L. Pravdo,Bryan P. Simpson,Sripriya Ravindra Kumar,Ken Y. Chan,Abhik Banerjee,Wei Li Wu,Bin Yang,Nina Huber,Sergiu P. Paşca,Viviana Gradinaru +10 more
TL;DR: This work uses Cre recombination–based AAV targeted evolution (CREATE) to generate AAV variants that efficiently and widely transduce the adult mouse central nervous system (CNS) after intravenous injection and demonstrates the potential of CREATE to produce customized AAV vectors for biomedical applications.
Journal ArticleDOI
Immune responses to AAV vectors: overcoming barriers to successful gene therapy
TL;DR: Careful immunosurveillance conducted as part of ongoing clinical studies will provide the basis for understanding the intricacies of the immune response in AAV-mediated gene transfer, facilitating safe and effective therapies for genetic diseases.
Journal ArticleDOI
State-of-the-art gene-based therapies: the road ahead.
TL;DR: Improvements in the gene transfer vectors used in therapeutic trials have led to substantial clinical successes in patients with serious genetic conditions, such as immunodeficiency syndromes, blindness and some cancer types.
Journal ArticleDOI
Engineering adeno-associated viruses for clinical gene therapy
TL;DR: New approaches to engineer and improve AAV vectors and their genetic cargo are increasingly helping to overcome barriers to extension of clinical gene therapy successes to many other human diseases.
References
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Journal ArticleDOI
Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response
Catherine S. Manno,Glenn F. Pierce,Valder R. Arruda,Bertil Glader,Margaret V. Ragni,Rasko Jj,Margareth C. Ozelo,Keith Hoots,Blatt P,Barbara A. Konkle,Michael D. Dake,Robin D. Kaye,Mahmood K. Razavi,A Zajko,James L. Zehnder,Pradip Rustagi,Hiroyuki Nakai,A Chew,Debra G.B. Leonard,Debra G.B. Leonard,J F Wright,Ruth Lessard,Jurg M. Sommer,Michael Tigges,Denise E. Sabatino,A Luk,Haiyan Jiang,Federico Mingozzi,Linda B. Couto,Hildegund C.J. Ertl,Katherine A. High,Katherine A. High,Mark A. Kay +32 more
TL;DR: In this article, a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B.
Journal ArticleDOI
Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
TL;DR: Vectors based on AAV7 and AAV8 should be considered for human gene therapy because of low reactivity to antibodies directed to human AAVs and because gene transfer efficiency in muscle was similar to that obtained with the best known serotype, whereas, in liver, gene transfer was substantially higher than previously described.
Journal ArticleDOI
Production of High-Titer Recombinant Adeno-Associated Virus Vectors in the Absence of Helper Adenovirus
TL;DR: The first rAAV production method which is completely free of adenovirus (Ad) helper virus is reported, which should facilitate a better understanding of immune response to AAV vectors in vivo, eliminate the need for developing replication-competent Ad assays, and provide a more defined reagent for clinical use.
Journal ArticleDOI
Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector
Mark A. Kay,Catherine S. Manno,Catherine S. Manno,Margaret V. Ragni,Peter J. Larson,Peter J. Larson,Linda B. Couto,Alan McClelland,Bertil Glader,Amy J. Chew,Shing J Tai,Roland W. Herzog,Valder R. Arruda,Fred Johnson,Ciaran Scallan,Erik D. Skarsgard,Alan W. Flake,Alan W. Flake,Katherine A. High,Katherine A. High +19 more
TL;DR: Evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.
Journal ArticleDOI
Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
Guangping Gao,Luk H. Vandenberghe,Mauricio R. Alvira,You Lu,Roberto Calcedo,Xiangyang Zhou,James M. Wilson +6 more
TL;DR: The potential for using Adeno-associated virus (AAV) as a vector for human gene therapy has stimulated interest in the Dependovirus genus as mentioned in this paper, although analyses of viruses and viral sequences from clinical samples are extremely limited.
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