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Titolo:
Expanding AAV packaging capacity with trans-splicing or overlapping vectors: A quantitative comparison
Autore:
Duan, DS; Yue, YP; Engelhardt, JF;
Indirizzi:
Univ Iowa, Coll Med, Dept Anat & Cell Biol, Iowa City, IA 52242 USA Univ Iowa Iowa City IA USA 52242 nat & Cell Biol, Iowa City, IA 52242 USA Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA Univ IowaIowa City IA USA 52242 pt Internal Med, Iowa City, IA 52242 USA Univ Iowa, Coll Med, Ctr Gene Therapy Cyst Fibrosis & Other Genet Dis, Iowa City, IA 52242 USA Univ Iowa Iowa City IA USA 52242 Other Genet Dis, Iowa City, IA 52242 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 4, volume: 4, anno: 2001,
pagine: 383 - 391
SICI:
1525-0016(200110)4:4<383:EAPCWT>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECOMBINANT ADENOASSOCIATED VIRUS; GENE-EXPRESSION; IN-VIVO; ADENOVIRUS; TRANSDUCTION; RECRUITMENT; CORECEPTOR; INFECTION; THERAPY; PROTEIN;
Keywords:
recombinant adeno-associated virus; rAAV; homologous recombination; circular intermediates; viral packaging; gene therapy; muscle; splicing;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Duan, DS Univ Iowa, Coll Med, Dept Anat & Cell Biol, Iowa City, IA 52242 USA Univ Iowa Iowa City IA USA 52242 l Biol, Iowa City, IA 52242 USA
Citazione:
D.S. Duan et al., "Expanding AAV packaging capacity with trans-splicing or overlapping vectors: A quantitative comparison", MOL THER, 4(4), 2001, pp. 383-391

Abstract

Recombinant adeno-associated (rAAV) viral vectors hold great therapeutic potential for human diseases. However, a relatively small packaging capacity(less than 5 kb) has limited the application of rAAV for certain diseases such as cystic fibrosis and Duchenne muscular dystrophy. Here we compared two mechanistically distinct approaches to overcome packaging restraints with rAAV vectors. The trans-splicing approach reconstitutes gene expression from two independent rAAV vectors, each encoding unique, nonoverlapping halves of a transgene. This process requires intermolecular concatamerization and subsequent splicing between independent vectors. A distinct overlapping vector approach uses homologous recombination between overlapping regions in two independent vectors. Using the p-galactosidase gene as template, trans-splicing approaches were threefold (in primary fibroblasts) and 12-fold (in muscle tissue) more effective in generating full-length transgene products than the overlapping vector approach. Nevertheless, the efficiency of trans-splicing remained moderate at approximately 4.3% (for muscle) and 7% (for fibroblasts) of that seen with a single vector encoding the full-length transgene. The efficiency of trans-splicing was augmented 185-fold by adenoviral E4, but not E2a, gene products. This augmentation was much less pronounced with the overlapping vectoring approach (12-fold). Transsplicing and overlapping vector approaches are two viable alternatives to expand rAAV packaging capacity.

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Documento generato il 02/04/20 alle ore 18:18:03