CFTR gene transduction in neonatal rabbits using anadeno-associated virus (AAV) vector

Rubenstein, RC; McVeigh, U; Flotte, TR; Guggino, W. B.; Zeitlin, PL

doi:10.1038/sj.gt.3300417

Cited by 46 publications

(23 citation statements)

References 6 publications

(11 reference statements)

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“…2 In the case of the rAAV2-cystic fibrosis transmembrane conductance regulator (rAAV2-CFTR) program, preclinical data in New Zealand white rabbits showed 6-month persistence of CFTR mRNA after endobronchial instillation. 3 Two additional studies were performed in rhesus macaques; the first indicated that rAAV2-CFTR delivery was relatively safe, although adeno-associated virus (AAV)2 vector genomes were found in the blood for a period of time after vector delivery. 4 The second study convincingly demonstrated that rAAV2-CFTR vector was not mobilized after concomitant wild-type AAV2 and adenovirus infection.…”

Section: Gene Therapy For Cystic Fibrosismentioning

confidence: 99%

Clinical gene therapy using recombinant adeno-associated virus vectors

2008

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Recombinant adeno-associated virus (rAAV) vectors possess a number of properties that may make them suitable for clinical gene therapy, including being based upon a virus for which there is no known pathology and a natural propensity to persist in human cells. Wild-type adeno-associated viruses (AAVs) are now known to be very diverse and ubiquitous in humans and nonhuman primates, which adds to the degree of confidence one may place in the natural history of AAV, namely that it has never been associated with any human tumors or other acute pathology, other than sporadic reports of having been isolated from spontaneously aborted fetuses. On the basis of this understanding of AAV biology and a wide range of preclinical studies in mice, rabbits, dogs and nonhuman primates, a growing number of clinical trials have been undertaken with this class of vectors. Altogether, over 40 clinical trials have now been approved. Although all previous trials were undertaken using AAV serotype 2 vectors, at least two current trials utilize AAV2 vector genomes cross-packaged or pseudotyped into AAV1 capsids, which appear to mediate more efficient gene delivery to muscle. The explosion of capsid isolates available for use as vectors to over 120 has now provided the potential to broaden the application of AAV-based gene therapy to other cell types.

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Section: Gene Therapy For Cystic Fibrosismentioning

confidence: 99%

Clinical gene therapy using recombinant adeno-associated virus vectors

2008

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“…21 In contrast, an AAV vector has not only been shown to infect airway cells efficiently, but the vector DNA persisted for weeks in animal models. 22,23 Recent phase I clinical trials also have shown delivery of the CFTR gene into epithelial cells. 24 The delivered CFTR cDNA persisted over 70 days based on PCR detection of vector DNA.…”

Section: Introductionmentioning

confidence: 99%

Efficient CFTR expression from AAV vectors packaged with promoters – the second generation

Wang

Fischer²,

Zhang

et al. 1999

Gene Ther

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Gene therapy studies of cystic fibrosis (CF) have shown ing capacity. Functional analyses showed that the new that AAV-based vector was efficient in transferring but not vectors were packaged efficiently and expressed higher in expressing the CFTR cDNA in the target cells. The levlevels of CFTR than a vector in which the CFTR gene was els of CFTR gene expression were limited by the small driven by the ITR sequence of AAV. Transduction of airway packaging capacity of AAV because it had been difficult to epithelial cells containing ٌ508 mutation with the new vecpackage the CFTR cDNA with an efficient promoter. In the tors demonstrated efficient expression of the wild-type present study we have developed a new generation of CFTR and correction of the CF phenotype. In contrast, no AAV/CFTR vectors which contain efficient short promoters significant CFTR expression was detected in cells infected to express the CFTR gene in target cells. To do so, we with the vector that express the CFTR gene from the ITR. reduced the size of the CFTR cDNA by determining the These findings support the notion that the AAV can be minimal untranslated regions required for expression of developed into an efficient vector to transduce the CFTR CFTR cDNA. We also identified short and efficient progene and vectors expressing higher levels of CFTR from moters that could be packaged with the down-sized CFTR an efficient promoter should provide better efficacy for cDNA into a novel AAV vector that had a maximal packaggene therapy of cystic fibrosis.

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“…[5][6][7] One explanation may be the marked changes occurring in the developing lung during the alveolar phase, with significant remodelling of the epithelium. Rubinstein et al 24 have suggested that this period, as well as the period following the alveolar phase, is associated with significant cell proliferation and differentiation from stem cells. They suggest that successful gene transfer of the airway epithelial cells may be 'diluted' if the vector is not propagated during cell mitosis or if the pulmonary epithelia are derived from 'new' stem cells.…”

Section: Discussionmentioning

confidence: 99%