Adeno-Associated Virus Serotype 6 Capsid Tyrosine-to-Phenylalanine Mutations Improve Gene Transfer to Skeletal Muscle
Chunping Qiao,Wei Zhang,Zhenhua Yuan,Jin Hong Shin,Jianbin Li,Giridhara R. Jayandharan,Li Zhong,Arun Srivastava,Xiao Xiao,Dongsheng Duan +9 more
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TLDR
The results suggest that tyrosine-mutant AAV6 vectors may represent powerful tools for testing muscle gene therapy in animal models and potentially in humans.Abstract:
Adeno-associated viral (AAV) vectors are the most efficient in vivo gene transfer tools for gene therapy applications. Efforts have been made to translate encouraging results in small animal models to human patients. However, the need for large quantities of vector for clinical application remains a great challenge. Developing novel AAV vectors with enhanced infectivity may reduce the high vector dose requirement for many applications such as gene therapy for muscular dystrophy. Selective mutation of AAV capsid surface-exposed tyrosine (Y) is a novel strategy to improve transduction efficiency. AAV6 has been considered one of the most robust muscle gene delivery vehicles. Here, we hypothesize that AAV6 transduction efficiency can be further enhanced by mutating surface Y to phenylalanine (F). We found that mutants AAV6-Y445F and AAV6-Y731F, especially the former, achieved more efficient gene transfer than the original AAV6 after intramuscular administration to mice. Expression of both firefly luciferase and alkaline phosphatase reporter genes increased up to 8-fold and DNA copy numbers in muscle increased up to 6-fold. Our results suggest that tyrosine-mutant AAV6 vectors may represent powerful tools for testing muscle gene therapy in animal models and potentially in humans.read more
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The AAV Vector Toolkit: Poised at the Clinical Crossroads
TL;DR: The discovery of naturally occurring adeno-associated virus isolates in different animal species and the generation of engineered AAV strains using molecular genetics tools have yielded a versatile AAV vector toolkit and a battery of second generation AAV vectors are now available.
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Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.
Terence R. Flotte,Bruce C. Trapnell,Margaret Humphries,Brenna Carey,Roberto Calcedo,Farshid N. Rouhani,Martha Campbell-Thompson,Anthony T. Yachnis,Robert A. Sandhaus,Noel G. McElvaney,Christian Mueller,Louis M. Messina,James M. Wilson,Mark L. Brantly,David R. Knop,Guo-jie Ye,Jeffrey D. Chulay +16 more
TL;DR: It is indicated that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved, and further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.
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Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy.
TL;DR: Preclinical data suggests that intravascular AAV micro-dystrophin delivery can significantly ameliorate muscle pathology, enhance muscle force, and attenuate dystrophic cardiomyopathy in animals.
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Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and Rat
Lawrence T. Bish,Kevin J. Morine,Margaret M. Sleeper,Julio Sanmiguel,Di Wu,Guangping Gao,James M. Wilson,H. Lee Sweeney +7 more
TL;DR: AAV9 provides high-level, stable expression in the mouse and rat heart and may provide a simple alternative to the creation of cardiac-specific transgenic mice and may be the vector of choice for clinical trials of cardiac gene transfer.
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Intracellular transport of recombinant adeno-associated virus vectors.
TL;DR: The current understanding of the mechanisms involved in rAAV attachment to target cells, endocytosis, intracellular trafficking, capsid processing, nuclear import and genome release are described with an emphasis on the most recent discoveries in the field and the emerging strategies used to improve the efficiency of AAV-derived vectors.
References
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Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial.
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Shyam Daya,Kenneth I. Berns +1 more
TL;DR: 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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