Efficient Gene Delivery to Pig Airway Epithelia and Submucosal Glands Using Helper-Dependent Adenoviral Vectors

被引：32

作者：

Cao, Huibi ^{[1
]}

Machuca, Tiago N. ^{[2
]}

Yeung, Jonathan C. ^{[2
]}

Wu, Jing ^{[1
]}

Du, Kai ^{[3
]}

Duan, Cathleen ^{[1
]}

Hashimoto, Kohei ^{[2
]}

Linacre, Virginia ^{[2
]}

Coates, Allan L. ^{[1
,4
]}

Leung, Kitty ^{[1
]}

Wang, Jian ^{[1
]}

Yeger, Herman ^{[3
]}

Cutz, Ernest ^{[3
]}

Liu, Mingyao ^{[2
]}

Keshavjee, Shaf ^{[2
]}

Hu, Jim ^{[1
,3
,4
]}

机构：

[1] Univ Toronto, Hosp Sick Children, Dept Physiol & Expt Med, Toronto, ON M5G 1X8, Canada

[2] Univ Toronto, Toronto Gen Res Inst, Univ Hlth Network, Latner Thorac Surg Res Labs,Div Thorac Surg, Toronto, ON M5G 1X8, Canada

[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1X8, Canada

[4] Univ Toronto, Dept Paediat, Toronto, ON M5G 1X8, Canada

来源：

MOLECULAR THERAPY-NUCLEIC ACIDS | 2013年 / 2卷

关键词：

cystic fibrosis; lung gene delivery; pig; FIBROSIS LUNG-DISEASE; TRANSMEMBRANE CONDUCTANCE REGULATOR; TARGETING TRANSGENE EXPRESSION; CYSTIC-FIBROSIS; CFTR EXPRESSION; CONGENITAL AMAUROSIS; RABBIT LUNG; THERAPY; MODEL; IDENTIFICATION;

D O I：

10.1038/mtna.2013.55

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF). However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR). Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.

引用

页数：10

共 41 条

[1]

Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency. [J].

Aiuti, Alessandro ;

Cattaneo, Federica ;

Galimberti, Stefania ;

Benninghoff, Ulrike ;

Cassani, Barbara ;

Callegaro, Luciano ;

Scaramuzza, Samantha ;

Andolfi, Grazia ;

Mirolo, Massimiliano ;

Brigida, Immacolata ;

Tabucchi, Antonella ;

Carlucci, Filippo ;

Eibl, Martha ;

Aker, Memet ;

Slavin, Shimon ;

Al-Mousa, Hamoud ;

Al Ghonaium, Abdulaziz ;

Ferster, Alina ;

Duppenthaler, Andrea ;

Notarangelo, Luigi ;

Wintergerst, Uwe ;

Buckley, Rebecca H. ;

Bregni, Marco ;

Marktel, Sarah ;

Valsecchi, Maria Grazia ;

Rossi, Paolo ;

Ciceri, Fabio ;

Miniero, Roberto ;

Bordignon, Claudio ;

Roncarolo, Maria-Grazia .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (05) :447-458

[2]

Effect of gene therapy on visual function in Leber's congenital amaurosis [J].

Bainbridge, James W. B. ;

Smith, Alexander J. ;

Barker, Susie S. ;

Robbie, Scott ;

Henderson, Robert ;

Balaggan, Kamaljit ;

Viswanathan, Ananth ;

Holder, Graham E. ;

Stockman, Andrew ;

Tyler, Nick ;

Petersen-Jones, Simon ;

Bhattacharya, Shomi S. ;

Thrasher, Adrian J. ;

Fitzke, Fred W. ;

Carter, Barrie J. ;

Rubin, Gary S. ;

Moore, Anthony T. ;

Ali, Robin R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (21) :2231-2239

[3]

CFTR involvement in chloride, bicarbonate, and liquid secretion by airway submucosal glands [J].

Ballard, ST ;

Trout, L ;

Bebök, Z ;

Sorscher, EJ ;

Crews, A .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1999, 277 (04) :L694-L699

[4]

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa [J].

Beltran, William A. ;

Cideciyan, Artur V. ;

Lewin, Alfred S. ;

Iwabe, Simone ;

Khanna, Hemant ;

Sumaroka, Alexander ;

Chiodo, Vince A. ;

Fajardo, Diego S. ;

Roman, Alejandro J. ;

Deng, Wen-Tao ;

Swider, Malgorzata ;

Aleman, Tomas S. ;

Boye, Sanford L. ;

Genini, Sem ;

Swaroop, Anand ;

Hauswirth, William W. ;

Jacobson, Samuel G. ;

Aguirre, Gustavo D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (06) :2132-2137

[5]

New concepts of the pathogenesis of cystic fibrosis lung disease [J].

Boucher, RC .

EUROPEAN RESPIRATORY JOURNAL, 2004, 23 (01) :146-158

[6]

Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression [J].

Cao, H. ;

Yang, T. ;

Li, X-F ;

Wu, J. ;

Duan, C. ;

Coates, A. L. ;

Hu, J. .

GENE THERAPY, 2011, 18 (02) :173-181

[7]

Targeting transgene expression to airway epithelia and submucosal glands, prominent sites of human CFTR expression [J].

Chow, YH ;

Plumb, J ;

Wen, YX ;

Steer, BM ;

Lu, Z ;

Buchwald, M ;

Hu, J .

MOLECULAR THERAPY, 2000, 2 (04) :359-367

[8]

Development of an epithelium-specific expression cassette with human DNA regulatory elements for transgene expression in lung airways [J].

Chow, YH ;

O'Brodovich, H ;

Plumb, J ;

Wen, YX ;

Sohn, KJ ;

Lu, Z ;

Zhang, FY ;

Lukacs, GL ;

Tanswell, AK ;

Hui, CC ;

Buchwald, M ;

Hu, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (26) :14695-14700

[9]

Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy [J].

Cideciyan, Artur V. .

PROGRESS IN RETINAL AND EYE RESEARCH, 2010, 29 (05) :398-427

[10]

Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year [J].

Cideciyan, Artur V. ;

Hauswirth, William W. ;

Aleman, Tomas S. ;

Kaushal, Shalesh ;

Schwartz, Sharon B. ;

Boye, Sanford L. ;

Windsor, Elizabeth A. M. ;

Conlon, Thomas J. ;

Sumaroka, Alexander ;

Pang, Ji-jing ;

Roman, Alejandro J. ;

Byrne, Barry J. ;

Jacobson, Samuel G. .

HUMAN GENE THERAPY, 2009, 20 (09) :999-1004

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