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Gene Delivery to Human Sweat Glands: a Model for Cystic fibrosis Gene Therapy

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Gene Delivery to Human Sweat Glands: a Model for Cystic fibrosis Gene Therapy Gene Therapy (2005) 12, 1752–1760 & 2005 Nature Publishing Group All rights reserved 0969-7128/05 $30.00 www.nature.com/gt RESEARCH ARTICLE Gene delivery to human sweat glands: a model for cystic fibrosis gene therapy H Lee1,2, DR Koehler1,3, CY Pang1,4,5, RH Levine5,PNg6, DJ Palmer6, PM Quinton7 and J Hu1,2,3 1Research Institute, The Hospital for Sick Children, Toronto, Canada; 2Institute of Medical Science, University of Toronto, Toronto, Canada; 3Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada; 4Department of Physiology, University of Toronto, Toronto, Canada; 5Department of Surgery, University of Toronto, Toronto, Canada; 6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; and 7Department of Pediatrics, UCSD School of Medicine University of California, San Diego, La Jolla, CA, USA Gene therapy vectors are mostly studied in cultured cells, application, intradermal injection or submerged culture. We rodents, and sometimes in non-human primates, but it is found that transduction efficiency can be enhanced by useful to test them in human tissue prior to clinical trials. pretreating isolated sweat glands with dispase, which In this study, we investigated the possibility of using human suggests that the basement membrane is a critical barrier sweat glands as a model for testing cystic fibrosis (CF) gene to gene delivery by adenoviral vectors. Using this approach, therapy vectors. Human sweat glands are relatively easy to we showed that Cftr could be efficiently delivered to and obtain from skin biopsy, and can be tested for CFTR function. expressed by the epithelial cells of sweat glands with our Using patients’ sweat glands could provide a safe model to helper-dependent adenoviral vector containing cytokeratin study the efficacy of CF gene therapy. As the first step to 18 regulatory elements. Based on this study we propose that explore using sweat glands as a model for CF gene therapy, sweat glands might be used as an alternative model to study we examined various ex vivo gene delivery methods for a CF gene therapy in humans. helper-dependent adenovirus (HD-Ad) vector. Gene delivery Gene Therapy (2005) 12, 1752–1760. doi:10.1038/ to sweat glands in skin organ culture was studied by topical sj.gt.3302587; published online 21 July 2005 Keywords: gene delivery; Cftr; sweat glands; native tissue; helper-dependent adenovirus vector; basement membrane Introduction Cftr mRNA to 5–10% could rescue the CF phenotype,5,6 although a recent review proposed that a higher level of Cystic fibrosis (CF), the most common genetic disorder in expression may be required at the protein level.7 In the Caucasian populations, is caused by recessive mutations last decade, adenovirus, adeno-associated virus (AAV) in the gene encoding the cystic fibrosis transmembrane and nonviral vectors were developed and used in CF conductance regulator (Cftr).1 CFTR is an ATP-binding gene therapy clinical trials.8 Gene therapy vectors are cassette (ABC) transporter that plays a critical role in salt mostly studied in cultured cells, rodents and other transport and fluid movement by controlling chloride animal models to verify their efficacy before clinical ion transport across epithelia.2 Dysfunction of CFTR trials. However, an appropriate animal model to study leads to disease in various organs including the CFTR functional correction in lung has not been achieved respiratory and digestive tracts. However, the complica- because Cftr knockout mice do not show the pulmonary tions in the lung caused by abnormal airway secretions, pathologic features observed in human CF lung.9 chronic infection and inflammation pose the most serious Although the Cftr knockout mouse models have been threat to CF patients.3 Currently, how the loss of CFTR utilized to evaluate the therapeutic potential of CF gene function causes the clinical manifestations and patholo- therapy,10–12 the lack of pathophysiology in the Cftr gical features of CF lung disease is not fully understood, knockout mouse lung limits the interpretation of experi- so treatment is focused on management of respiratory mental results from CF mouse models. Therefore, an infection and inflammation in the lung.4 alternative model using a native human tissue is CF is considered one of the diseases that could be critically needed to assess the efficacy of CF gene therapy. treated by gene therapy because it is a single gene The eccrine sweat gland (referred to as ‘sweat gland’ disorder and the vector can be delivered directly to the below) is one of the organs affected by CF. The sweat lung through the airway. Moreover, restoration of normal gland is one of the smallest organs in the human body, uniquely developed in humans to control body tempera- ture by evaporation. It has a simple tubular structure Correspondence: Dr J Hu, Lung Biology Research Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada M5G 1X8 with only 2–3 layers of cells. Isotonic primary sweat is Received 20 March 2005; accepted 13 June 2005; published online produced in the lower part of the sweat gland called the 21 July 2005 secretory coil, and, as the primary sweat moves to the Gene delivery to human sweat glands H Lee et al 1753 skin surface through the sweat duct, electrolytes are culture). After 2 days of exposure to the vector, the skin reabsorbed by the epithelial cells from the apical tissue was assayed for b-galactosidase activity deter- membrane. CFTR plays an important role in sweat mined by reaction with X-gal. The transduction effi- secretion and salt reabsorption in sweat glands,13 and ciency was very low and only a few cells in a few sweat its dysfunction in CF patients results in salty sweat. The glands stained with X-gal (Supplementary data, Figure abnormal sweat composition in CF patients can be 8). Those few transduced sweat glands were observed detected by a ‘sweat test’, a common diagnostic method only in the intradermally injected or submersion organ used in CF clinics. Sweat glands do not manifest the cultures. No sweat gland transduction was observed by anatomical alterations or pathology observed in other topical application of virus to skin in air–liquid interface organs affected in the disease, and have been used as a culture. model to study CFTR function and electrolyte transport Most transduced sweat glands were found at sites pathophysiology.14,15 where they had been directly exposed to virus. For There are a number of advantages in using human example, transduced sweat glands were found at the sweat glands as a model to study CF. They are relatively immediate site of the injection or at the excised periphery easy to access from a skin punch biopsy, and the function of the skin tissue in the submerged culture. This of CFTR can be measured electrophysiologically in the observation indicated that the adenovirus vector has apical membrane of the sweat duct ex vivo.16 With these limited ability to penetrate and transduce skin tissue advantages, sweat glands could be a useful model to in the organ culture. In order to increase the number of assess efficacy of CF gene therapy. Delivery and exposed sweat glands from the dermis, we treated the expression of normal Cftr to CF sweat glands is expected skin tissue with collagenase. Although collagenase to restore the normal chloride transport function. Thus, it partially digested the collagen-rich dermal matrix, it left should be possible to evaluate the effectiveness of gene the tissue sticky and did not noticeably increase the transfer and expression by the secretory response, transduction efficiency. Nonetheless, we found that a biochemical analyses of the sweat, or electrophysiologi- few sweat glands at the periphery of the tissue, which cal properties according to well-established methods.16 were completely freed from the dermal matrix by the Furthermore, using sweat glands in studying CF gene collagenase treatment, were transduced by the adenovir- therapy has significant implications for CF clinical trials. al vector (Figure 1). These results using skin organ It is inherently safer and more practical to administer culture suggested that the epidermis and dermal matrix gene therapy vectors to a small punch biopsy or to a are significant barriers to adenoviral vectors. small region of skin, rather than to CF affected organs such as pancreas or lung. However, whether genes can Gene delivery to isolated sweat glands be effectively delivered to human sweat glands remains In an attempt to circumvent the barriers in skin tissue, to be shown. Although sweat glands may provide an we isolated sweat glands from the dermis by mechani- important model to study the effect of CF gene therapy cally mincing the skin.18 The isolated sweat glands were in human native tissues, differences in morphology then incubated with HD-Ad vectors added to the media. and physiology exist between the sweat gland and Inoculating HDD28E4LacZ17 (5 Â 1010 viral particles) into the lung. 100 ml media containing isolated sweat glands appeared As a first step to explore the possibility of using sweat to increase the transduction and expression of the glands as a model for CF gene therapy, we investigated transgene in the sweat glands, highlighted by the large effective gene delivery methods using normal human area of X-gal staining (Figure 2a). However, when the sweat glands. We showed that transgenes can be histologic sections were examined most of the lacZ efficiently delivered to the sweat gland cells by adeno- positive cells were found at the outer layer of the viral gene therapy vectors. Furthermore, Cftr was transduced sweat glands (Figure 2b). In fact, most of the delivered to, and expressed by, the target cells in the X-gal staining was in the remnant interstitial tissue, lumen of sweat glands using a helper-dependent indicating that the HD-Ad did not penetrate to the inner adenovirus (HD-Ad) vector containing an epithelial layer of cells of the sweat gland when applied from the cell-specific promoter.
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