Viral Vector–mediated and Cell-based Therapies for Treatment of Cystic Fibrosis

Flotte, Terence R.; Ng, Philip; Dylla, Douglas E.; McCray, Paul B.; Wang, Guoshun; Kolls, Jay K.; Hu, Jim

doi:10.1038/sj.mt.6300002

Cited by 62 publications

(52 citation statements)

References 195 publications

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“…This result supports the theory that a highly infectious phenotype may be evolutionarily deleterious, and, therefore, naturally evolved viruses likely fail to possess optimal phenotypes for highly efficient respiratory gene delivery vectors (3,22). Our experimental system with artificial selective pressures thus enabled the evolution of a novel viral variant with a specific phenotype (i.e., enhanced infectivity) by removing natural viral evolutionary pressures and constraints, such as host survival and long transmission times.…”

Section: Discussionsupporting

confidence: 66%

“…To achieve evolutionary success, viruses may alter or compromise each of these steps to reduce the efficiency of infection and achieve a balance between the production of viruses that spread, but do not cause, host (and hence virus) extinction. This concept is strikingly illustrated by the inefficiency, and consequent lack of therapeutic end points, of gene transfer vectors based on respiratory viruses for respiratory diseases (3)(4)(5)(6). A better understanding of evolutionary principles governing natural viral evolution will drive more advanced methods to successfully engineer novel virus-based gene therapeutics.…”

mentioning

confidence: 99%

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Directed evolution of adeno-associated virus to an infectious respiratory virus

Excoffon

Koerber²,

Dickey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

155

180

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Respiratory viruses evolve to maintain infectivity levels that permit spread yet prevent host and virus extinction, resulting in surprisingly low infection rates. Respiratory viruses harnessed as gene therapy vectors have illustrated this limitation. We used directed evolution in an organotypic human airway model to generate a highly infectious adeno-associated virus. This virus mediated gene transfer more than 100-fold better than parental strains and corrected the cystic fibrosis epithelial Cl ؊ transport defect. Thus, under appropriate selective pressures, viruses can evolve to be more infectious than observed in nature, a finding that holds significant implications for designing vectors for gene therapy and for understanding emerging pathogens.

show abstract

Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Directed evolution of adeno-associated virus to an infectious respiratory virus

Excoffon

Koerber²,

Dickey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

155

180

View full text Add to dashboard Cite

show abstract

“…In addition to T-cell-mediated immune responses, NAB development is another major limitation of viral vectors and inhibits vector readministration. 1,3 Previous studies addressing repeated dosing with rAAV vectors have provided contradicting data. Successful repeated administration after pretreatment of the host with immunosuppressing antibodies, 19 and/or immunemodulating agents 20 or broad immunosuppressing agents, 21 has been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Of the many vectors used, adeno-associated virus (AAV)-based vectors hold great promise for efficiently targeting airway epithelium in vivo. 1 Major interest in AAV vectors has been evoked due to their lack of pathogenicity, ability to transduce non-dividing cells, 2 prolonged transgene expression and low immunogenicity. 3 Initial studies using recombinant AAV (rAAV) vectors were primarily focused on serotype 2.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Gene therapy holds great potential for the treatment of various acquired and inherited pulmonary diseases. Among various viral vectors, adeno-associated viral (AAV) vectors have been most frequently used in different clinical trials of pulmonary gene therapy. In the present study, we examined the kinetics and duration of transgene expression, vector biodistribution and development of neutralizing antibodies (NAB) in mice after pulmonary application of AAV2/9 vector. The pulmonary route of application did not affect any of the measured parameters. Transgene expression and biodistribution analysis at day 450 post-application confirmed the systemic spread of the vector after pulmonary delivery. Using SPB À/À mice, the study shows that AAV2/9-mediated gene expression is influenced by animal gender but not mouse genotype and is insensitive to the presence of lung inflammation. Lower expression levels were observed in male compared with female mice, and transient immunosuppression with dexamethasone significantly reduced the development of NAB in both genders of mice. The study thus advances this serotype for further development and use as a therapeutic vector.

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“…Over the last decade, immense research has been conducted on improving the vector design, which has resulted in development of helper-dependent adenoviral (HD-Ad) 3 vectors, which do not encode any viral genes. The only viral sequences present are the terminal repeats along with the packaging signal (2). This has resulted in HD-Ad vectors being selected as the vector of choice for pulmonary gene therapy for diseases such as cystic fibrosis (3)(4)(5).…”

Section: Characterization Of Pulmonary T Cell Response Tomentioning

confidence: 99%

Characterization of Pulmonary T Cell Response to Helper-Dependent Adenoviral Vectors following Intranasal Delivery

Kushwah

Cao

2008

The Journal of Immunology

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In spite of the extensive research in the field of gene therapy, host immune responses continue to be the major barrier in translating basic research to clinical practice. Helper-dependent adenoviral (HD-Ad) vectors show great potential for pulmonary gene therapy, but the knowledge of pulmonary immune responses toward these vectors is very limited. In this study, we show that HD-Ad vectors are potent stimulators of dendritic cell (DC) maturation, thus leading to stimulation of T cell proliferation with ∼6% of naive CD4+ T cells from pulmonary mediastinal lymph node responding to HD-Ad-treated DCs. In contrast to the belief that HD-Ad vectors are unable to prime adaptive immune response, we show for the first time, through in vivo pulmonary studies in mice, that HD-Ad vectors can prime CD4+ and CD8+ T cell responses in the lung at high and substantially low doses. This indicates cross-presentation of HD-Ad-derived epitopes by DCs to prime CD8+ T cell responses. To assess the basis of pulmonary T cell response against HD-Ad vectors, we examined the response of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) in the lung. In response to HD-Ad delivery, there is induction of maturation in both cDC and pDC subsets, but it is the cDCs, not pDCs, that migrate rapidly to draining lymph nodes within the first 2 days after vector delivery to prime adaptive immune response against these vectors. These findings have implications for development of strategies to prevent adaptive immune responses against gene therapy vectors.

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Viral Vector–mediated and Cell-based Therapies for Treatment of Cystic Fibrosis

Cited by 62 publications

References 195 publications

Directed evolution of adeno-associated virus to an infectious respiratory virus

Directed evolution of adeno-associated virus to an infectious respiratory virus

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

Characterization of Pulmonary T Cell Response to Helper-Dependent Adenoviral Vectors following Intranasal Delivery

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