scholarly journals Inflammation Promotes the Loss of Adeno-Associated Virus–Mediated Transgene Expression in Mouse Liver

2011 ◽  
Vol 141 (1) ◽  
pp. 348-357.e3 ◽  
Author(s):  
Ekaterina Breous ◽  
Suryanarayan Somanathan ◽  
Peter Bell ◽  
James M. Wilson
Keyword(s):  
Mouse Liver ◽  
Transgene Expression ◽  
Adeno Associated Virus

scholarly journals Evading the AAV Immune Response in Mucopolysaccharidoses

2020 ◽  
Vol 21 (10) ◽  
pp. 3433
Author(s):  
Matthew Piechnik ◽  
Kazuki Sawamoto ◽  
Hidenori Ohnishi ◽  
Norio Kawamoto ◽  
Yasuhiko Ago ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Humoral Immune Response ◽  
Transgene Expression ◽  
Evidence Based ◽  
Adeno Associated Virus ◽  
Gene Therapies ◽  
Humoral Immune ◽  
Significant Challenge ◽  
Racial Background

The humoral immune response elicited by adeno-associated virus (AAV)-mediated gene therapy for the treatment of mucopolysaccharidoses (MPS) poses a significant challenge to achieving therapeutic levels of transgene expression. Antibodies targeting the AAV capsid as well as the transgene product diminish the production of glycosaminoglycan (GAG)-degrading enzymes essential for the treatment of MPS. Patients who have antibodies against AAV capsid increase in number with age, serotype, and racial background and are excluded from the clinical trials at present. In addition, patients who have undergone AAV gene therapy are often excluded from the additional AAV gene therapy with the same serotype, since their acquired immune response (antibody) against AAV will limit further efficacy of treatment. Several methods are being developed to overcome this immune response, such as novel serotype design, antibody reduction by plasmapheresis and immunosuppression, and antibody evasion using empty capsids and enveloped AAV vectors. In this review, we examine the mechanisms of the anti-AAV humoral immune response and evaluate the strengths and weaknesses of current evasion strategies in order to provide an evidence-based recommendation on evading the immune response for future AAV-mediated gene therapies for MPS.

scholarly journals Five Years of Successful Inducible Transgene Expression Following Locoregional Adeno-Associated Virus Delivery in Nonhuman Primates with No Detectable Immunity

2019 ◽  
Vol 30 (7) ◽  
pp. 802-813 ◽  
Author(s):  
Mickaël Guilbaud ◽  
Marie Devaux ◽  
Celia Couzinié ◽  
Johanne Le Duff ◽  
Alice Toromanoff ◽  
...  
Keyword(s):  
Transgene Expression ◽  
Nonhuman Primates ◽  
Adeno Associated Virus ◽  
Virus Delivery

One year transgene expression with adeno-associated virus cardiac gene transfer

2005 ◽  
Vol 100 (3) ◽  
pp. 421-426 ◽  
Author(s):  
Y. Joseph Woo ◽  
Janet C.L. Zhang ◽  
Matthew D. Taylor ◽  
Jeffrey E. Cohen ◽  
Vivian M. Hsu ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Transgene Expression ◽  
Adeno Associated Virus ◽  
Cardiac Gene ◽  
One Year

scholarly journals DNA Palindromes with a Modest Arm Length of ≳20 Base Pairs Are a Significant Target for Recombinant Adeno-Associated Virus Vector Integration in the Liver, Muscles, and Heart in Mice

2007 ◽  
Vol 81 (20) ◽  
pp. 11290-11303 ◽  
Author(s):  
Katsuya Inagaki ◽  
Susanna M. Lewis ◽  
Xiaolin Wu ◽  
Congrong Ma ◽  
David J. Munroe ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Integration Site ◽  
Marker Gene ◽  
Cpg Islands ◽  
Previous Method ◽  
Adeno Associated Virus ◽  
Transcription Start Sites ◽  
Vector Integration ◽  
Integration Sites

ABSTRACT Our previous study has shown that recombinant adeno-associated virus (rAAV) vector integrates preferentially in genes, near transcription start sites and CpG islands in mouse liver (H. Nakai, X. Wu, S. Fuess, T. A. Storm, D. Munroe, E. Montini, S. M. Burgess, M. Grompe, and M. A. Kay, J. Virol. 79:3606-3614, 2005). However, the previous method relied on in vivo selection of rAAV integrants and could be employed for the liver but not for other tissues. Here, we describe a novel method for high-throughput rAAV integration site analysis that does not rely on marker gene expression, selection, or cell division, and therefore it can identify rAAV integration sites in nondividing cells without cell manipulations. Using this new method, we identified and characterized a total of 997 rAAV integration sites in mouse liver, skeletal muscle, and heart, transduced with rAAV2 or rAAV8 vector. The results support our previous observations, but notably they have revealed that DNA palindromes with an arm length of ≳20 bp (total length, ≳40 bp) are a significant target for rAAV integration. Up to ∼30% of total integration events occurred in the vicinity of DNA palindromes with an arm length of ≳20 bp. Considering that DNA palindromes may constitute fragile genomic sites, our results support the notion that rAAV integrates at chromosomal sites susceptible to breakage or preexisting breakage sites. The use of rAAV to label fragile genomic sites may provide an important new tool for probing the intrinsic source of ongoing genomic instability in various tissues in animals, studying DNA palindrome metabolism in vivo, and understanding their possible contributions to carcinogenesis and aging.

scholarly journals Persistent transgene expression in mouse liver following in vivo gene transfer with a ΔE1/ΔE4 adenovirus vector

Gene Therapy ◽  
1997 ◽  
Vol 4 (5) ◽  
pp. 393-400 ◽  
Author(s):  
Q Wang ◽  
G Greenburg ◽  
D Bunch ◽  
D Farson ◽  
MH Finer
Keyword(s):  
Gene Transfer ◽  
Mouse Liver ◽  
Transgene Expression ◽  
Adenovirus Vector ◽  
In Vivo Gene Transfer

scholarly journals Lack of Repeat Transduction by Recombinant Adeno-Associated Virus Type 5/5 Vectors in the Mouse Airway

2007 ◽  
Vol 81 (22) ◽  
pp. 12360-12367 ◽  
Author(s):  
Stephanie G. Sumner-Jones ◽  
Deborah R. Gill ◽  
Stephen C. Hyde
Keyword(s):  
Transgene Expression ◽  
Lung Diseases ◽  
Repeated Administration ◽  
Transduction Efficiency ◽  
Viral Gene ◽  
Rapid Rise ◽  
Adeno Associated Virus ◽  
Subsequent Failure

ABSTRACT While recombinant adeno-associated virus (rAAV) vectors promote long-term transgene expression in the lungs and other organs, the goal of correcting chronic inherited lung diseases such as cystic fibrosis with this type of viral gene transfer vector is limited by the requirement of achieving stable potent transgene expression, potentially requiring vector readministration. Here we evaluated the abilities of rAAV type 5/5 (rAAV5/5) vectors based on the genome and capsid of AAV5 to efficiently transduce the lungs and nasal epithelium of mice after repeated administration. Transduction efficiency as judged by reporter gene expression was markedly reduced on a second rAAV5/5 administration and effectively abolished on a third. Varying the period between administrations from 8 to 36 weeks did not allow efficient repeated administration. A rapid rise in anti-AAV5 antibodies was noted after rAAV5/5 vector administration that was sustained for the entire period of investigation (in some cases exceeding 9 months). Furthermore, this antibody response and subsequent failure to repeatedly administer the vector were not rescued by the in vivo expression of CTLA4Ig from an rAAV5/5 vector. These results suggest that without the development of an effective and clinically acceptable immunosuppression strategy, treatments for chronic diseases that require repeated administration of rAAV5/5 vectors will be unsuccessful.

scholarly journals Isolation of Recombinant Adeno-Associated Virus Vector-Cellular DNA Junctions from Mouse Liver

1999 ◽  
Vol 73 (7) ◽  
pp. 5438-5447 ◽  
Author(s):  
Hiroyuki Nakai ◽  
Yuichi Iwaki ◽  
Mark A. Kay ◽  
Linda B. Couto
Keyword(s):  
Portal Vein ◽  
Dna Sequences ◽  
Mouse Liver ◽  
Host Genome ◽  
Vector System ◽  
Rrna Gene ◽  
Raav Vector ◽  
Adeno Associated Virus ◽  
Dna Junctions ◽  
Cellular Dna

ABSTRACT Recombinant adeno-associated virus (rAAV) vectors allow for sustained expression of transgene products from mouse liver following a single portal vein administration. Here a rAAV vector expressing human coagulation factor F.IX (hF.IX), AAV-EF1α-F.IX (hF.IX expression was controlled by the human elongation factor 1α [EF1α] enhancer-promoter) was injected into mice via the portal vein or tail vein, or directly into the liver parenchyma, and the forms of rAAV vector DNA extracted from the liver were analyzed. Southern blot analyses suggested that rAAV vector integrated into the host genome, forming mainly head-to-tail concatemers with occasional deletions of the inverted terminal repeats (ITRs) and their flanking sequences. To further confirm vector integration, we developed a shuttle vector system and isolated and sequenced rAAV vector-cellular DNA junctions from transduced mouse livers. Analysis of 18 junctions revealed various rearrangements, including ITR deletions and amplifications of the vector and cellular DNA sequences. The breakpoints of the vector were mostly located within the ITRs, and cellular DNA sequences were recombined with the vector genome in a nonhomologous manner. Two rAAV-targeted DNA sequences were identified as the mouse rRNA gene and the α1 collagen gene. These observations serve as direct evidence of rAAV integration into the host genome of mouse liver and allow us to begin to elucidate the mechanisms involved in rAAV integration into tissues in vivo.

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