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.
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Abstract: Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.
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References
Characterization of Adeno-Associated Virus Genomes Isolated from Human Tissues
TL;DR: A novel amplification assay was used to show that the majority of wild-type AAV DNA existed as circular double-stranded episomes in human tissues, consistent with the circular episomal forms of recombinant AAV vectors that have been isolated and characterized from in vivo transduced tissues.
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Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison.
TL;DR: Using the beta-galactosidase gene as template, trans-splicing approaches were threefold and 12-fold more effective in generating full-length transgene products than the overlapping vector approach.
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Adeno-Associated Virus-Based Gene Therapy for CNS Diseases
TL;DR: The purpose of this review is to describe the most notable advancements in preclinical and clinical research on AAV-based CNS gene therapy and to discuss prospects for future development based on a new generation of vectors and delivery.
271
Promoterless gene targeting without nucleases ameliorates haemophilia B in mice
Adi Barzel,Nicole K. Paulk,Yufang Shi,Yong Huang,Kirk Chu,Feijie Zhang,Paul N. Valdmanis,Laura P. Spector,Matthew H. Porteus,Karin M.L. Gaensler,Mark A. Kay +10 more
TL;DR: Transgene integration as a 2A-fusion to a highly expressed endogenous gene may obviate the requirement for nucleases and/or vector-borne promoters, and may allow for safe and efficacious gene targeting in both infants and adults by greatly diminishing off-target effects while still providing therapeutic levels of expression from integration.
Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma.
Christine E. Brown,Brenda Aguilar,Renate Starr,Xin Yang,Wen-Chung Chang,Lihong Weng,Brenda Chang,Aniee Sarkissian,Alfonso Brito,James F. Sanchez,Julie R. Ostberg,Massimo D'Apuzzo,Behnam Badie,Michael E. Barish,Stephen J. Forman +14 more
TL;DR: The optimization of IL13Rα2-targeted CAR T cells are described, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T-cells, which help define parameters for the clinical translation of CAR T-cell therapy for the treatment of brain tumors.
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