Viral serotype and the transgene sequence influence overlapping adeno‐associated viral (AAV) vector‐mediated gene transfer in skeletal muscle

Ghosh, Arkasubhra; Yue, Yongping; Duan, Dongsheng

doi:10.1002/jgm.835

Cited by 57 publications

(58 citation statements)

References 47 publications

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“…In this latter case, a large open reading frame is split into 2 different rAAV vectors. Reconstitution of a single protein depends on efficient infection of the same cell by the 2 rAAVs, intermolecular rejoining of their genomes, and expression of a single protein either by homologous recombination through overlapping sequences (31) or by trans-splicing of a common reconstituted transcript (32).…”

Section: Discussionmentioning

confidence: 99%

Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice

Allocca¹,

Doria²,

Petrillo³

et al. 2008

J. Clin. Invest.

258

218

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Vectors derived from adeno-associated virus (AAV) are promising for human gene therapy, including treatment for retinal blindness. One major limitation of AAVs as vectors is that AAV cargo capacity has been considered to be restricted to 4.7 kb. Here we demonstrate that vectors with an AAV5 capsid (i.e., rAAV2/5) incorporated up to 8.9 kb of genome more efficiently than 6 other serotypes tested, independent of the efficiency of the rAAV2/5 production process. Efficient packaging of the large murine Abca4 and human MYO7A and CEP290 genes, which are mutated in common blinding diseases, was obtained, suggesting that this packaging efficiency is independent of the specific sequence packaged. Expression of proteins of the appropriate size and function was observed following transduction with rAAV2/5 carrying large genes. Intraocular administration of rAAV2/5 encoding ABCA4 resulted in protein localization to rod outer segments and significant and stable morphological and functional improvement of the retina in Abca4 -/-mice. This use of rAAV2/5 may be a promising therapeutic strategy for recessive Stargardt disease, the most common form of inherited macular degeneration. The possibility of packaging large genes in AAV greatly expands the therapeutic potential of this vector system.

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Section: Discussionmentioning

confidence: 99%

Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice

Allocca¹,

Doria²,

Petrillo³

et al. 2008

J. Clin. Invest.

258

218

View full text Add to dashboard Cite

show abstract

“…This application becomes useful for using AAV to deliver therapeutic genes up to 9 kb in size. trans splicing has been successfully used for gene expression in the retina (55), the lung (39), and, more recently, muscle (25). trans-Splicing vectors are less efficient than rAAV vectors.…”

Section: Aav As a Gene Therapy Vectormentioning

confidence: 99%

Gene Therapy Using Adeno-Associated Virus Vectors

2008

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SUMMARY The unique life cycle of adeno-associated virus (AAV) and its ability to infect both nondividing and dividing cells with persistent expression have made it an attractive vector. An additional attractive feature of the wild-type virus is the lack of apparent pathogenicity. Gene transfer studies using AAV have shown significant progress at the level of animal models; clinical trials have been noteworthy with respect to the safety of AAV vectors. No proven efficacy has been observed, although in some instances, there have been promising observations. In this review, topics in AAV biology are supplemented with a section on AAV clinical trials with emphasis on the need for a deeper understanding of AAV biology and the development of efficient AAV vectors. In addition, several novel approaches and recent findings that promise to expand AAV's utility are discussed, especially in the context of combining gene therapy ex vivo with new advances in stem or progenitor cell biology.

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“…To circumvent this problem, we initially targeted two different organs: liver for piZZ knockdown and muscle for wild-type AAT replacement. We chose to use AAV6 for intramuscular injection, as this AAV serotype is considered one of the best for initiating transgene expression in muscles (8). After injection of AAV8/shRNA2 vector systemically in piZZ mice, AAV6/AAT was injected into muscle.…”

Section: Muscular Administration Of Aav6/aat Restored Aat Expression mentioning

confidence: 99%

Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins

Xiao

Gray

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Molecular knockdown of disease proteins and restoration of wildtype activity represent a promising but challenging strategy for the treatment of diseases that result from the accumulation of misfolded proteins (i.e., Huntington disease, amyotrophic lateral sclerosis, and α-1 antitrypsin deficiency). In this study we used alpha-1 antitrypsin (AAT) deficiency with the piZZ mutant phenotype as a model system to evaluate the efficiency of gene-delivery approaches that both silence the piZZ transcript (e.g., shRNA) and restore circulating wild-type AAT expression from resistant codonoptimized AAT (AAT-opt) transgene cassette using adeno-associated virus (AAV) vector delivery. After systemic injection of a selfcomplimentary AAV serotype 8 (scAAV8) vector encoding shRNA in piZZ transgenic mice, both mutant AAT mRNA in the liver and defected serum protein level were inhibited by 95%, whereas liver pathology, as monitored by dPAS and fibrosis staining, reversed. To restore blood AAT levels in AAV8/shRNA-treated mice, several strategies to restore functional AAT levels were tested, including using AAV AAT-opt transgene cassettes targeted to muscle and liver, or combination vectors carrying piZZ shRNA and AAT-opt transgenes separately, or a single bicistronic AAV vector. With these molecular approaches, we observed over 90% knockdown of mutant AAT with a 13-to 30-fold increase of circulating wildtype AAT protein from the shRNA-resistant AAT-opt cassette. The molecular approaches applied in this study can simultaneously prevent liver pathology and restore blood AAT concentration in AAT deficiencies. Based on these observations, similar gene-therapy strategies could be considered for any diseases caused by accumulation of misfolded proteins.neurodegenerative disease | codon modification | mutant protein | therapeutic | dPAS staining

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Viral serotype and the transgene sequence influence overlapping adeno‐associated viral (AAV) vector‐mediated gene transfer in skeletal muscle

Cited by 57 publications

References 47 publications

Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice

Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice

Gene Therapy Using Adeno-Associated Virus Vectors

Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins

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