Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered

Abstract

Airway-directed gene transfer has emerged as a promising approach for the treatment of the two genetic diseases of the lung, namely cystic fibrosis and α-1-antitrypsin deficiency. Herein we describe the transduction efficiency of a novel adeno-associated virus (AAV) vector, AAV2/9, across murine nasal and lung airway epithelia. At the peak of gene expression AAV2/9-mediated human α-1-antitrypsin gene expression in serum was ≈60-fold better than that of AAV2/5. We found that AAV2/9-mediated n LacZ gene transfer in nasal and lung airways was relatively stable for 9 months, suggesting that a progenitor airway cell population was transduced. Most interestingly, we show that AAV2/9 can be readministered in the presence of high levels of serum-circulating neutralizing antibodies as early as 1 month after initial exposure, with minimal effect on overall reporter gene expression, rendering it a promising gene transfer vector candidate for use in humans.

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…In contrast, AAV5 was neutralized resulting in abrogated transgene expression upon secondary exposure. 78 …”

Jaagsiekte sheep retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung

“…In adult mice, AAV efficiently transduced respiratory epithelium for up to 9 months, although a steady decline in transgene expression was reported. 22 Because AAV vectors designed for gene therapy have a low frequency of integration into the host genome, transgene expression is gradually lost through cell division. Another major drawback of AAV vectors is their limited packaging capacity (B4.7 Kb), which precludes insertion of some full-length therapeutic genes required to treat lung diseases such as cystic fibrosis and SP-B deficiency.…”

Adeno-associated virus serotype 9-mediated pulmonary transgene expression: effect of mouse strain, animal gender and lung inflammation

“…4 The advent of technology for pseudotyping has provided the means to bypass this limitation of receptors and the prevalence of neutralizing antibodies (NAB) to AAV2. 5,8 Numerous serotypes of rAAV have supported persistent transgene expression after pulmonary gene delivery. 6,[9][10][11][12][13][14] A recent study comparing different AAV serotypes in vivo in murine lungs and in vitro in human ciliated airway epithelium found AAV1, 6 and 9 to be highly efficient.…”