Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

He, X; Goldsmith, Corinne M.; Marmary, Yitzhak; Wellner, Robert B.; Parlow, A.F.; Nieman, Lynnette K.; Baum, Bruce J.

doi:10.1038/sj.gt.3300622

Cited by 88 publications

(104 citation statements)

References 22 publications

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“…First-generation, E1 − , recombinant adenoviruses (serotype 5) encoding either hEpo (AdCMVhEpo), hEpo-hGH (AdCMVhEpo-hGH), hGH-hEpo (AdCMVhGH-hEpo), or hGH (AdCMVhGH) were constructed as previously reported [25] by contransfection of the shuttle plasmid pAC-CMV-pLpA with the corresponding transgenes, together with the adenoviral plasmid pJM17 into 293 human embryonic kidney (HEK) cells. The vectors were amplified in HEK 293 cells and purified by two rounds of CsCl gradient centrifugation as described [26].…”

Section: Recombinant Adenoviral Vectormentioning

confidence: 99%

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

Samuni

Zheng

Cawley

et al. 2008

Biochemical and Biophysical Research Communications

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Neuroendocrine and exocrine cells secrete proteins in either a constitutive manner or via the regulated secretory pathway (RSP), but the specific sorting mechanisms involved are not fully understood. After gene transfer to rat salivary glands, the transgenic model proteins human growth hormone (hGH) and erythropoietin (hEpo) are secreted primarily into saliva (RSP; exocrine) and serum (constitutive; endocrine), respectively. We hypothesized that fusion of hGH at either the C-terminus or the N-terminus of hEpo would re-direct hEpo from the bloodstream into saliva. We constructed and expressed two fusion proteins, hEpo-hGH and hGH-hEpo, using serotype 5-adenoviral vectors, and delivered them to rat submandibular glands in vivo via retroductal cannulation. Both the hEpohGH and hGH-hEpo fusion proteins, but not hEpo alone, were secreted primarily into saliva (p<0.0001 and P=0.0083, respectively). These in vivo studies demonstrate for the first time that hGH, in an N-as well as C-terminal position, influences the secretion of a constitutive pathway protein.

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Section: Recombinant Adenoviral Vectormentioning

confidence: 99%

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

Samuni

Zheng

Cawley

et al. 2008

Biochemical and Biophysical Research Communications

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“…Nonetheless, we and others were sufficiently intrigued by this existing body of information to propose a unique application of gene transfer technology to salivary glands; treating systemic single protein deficiency disorders through the endocrine secretion of transgenic secretory proteins (systemic gene therapeutics; Kagami et al, 1996;Goldfine et al, 1997;Wang et al, 1997;He et al, 1998;Niedzinski et al, 2003, see below).…”

Section: Evidence Of Endocrine Secretion From Salivary Glandsmentioning

confidence: 99%

Utilizing endocrine secretory pathways in salivary glands for systemic gene therapeutics

Voutetakis

Wang

Baum

2003

Journal Cellular Physiology

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Mammalian salivary glands are commonly used models of exocrine secretion. However, there is substantial experimental evidence showing the physiological existence of endocrine secretory pathways in these tissues. The use of gene transfer technology in vivo has allowed the unambiguous demonstration of these endocrine pathways. We and others have exploited such findings and evaluated salivary glands as possible target tissues for systemic applications of gene therapeutics. Salivary glands present numerous advantages for this purpose, including being well encapsulated, which limits extra-glandular vector dissemination, and having the luminal membranes of almost all parenchymal cells accessible via intraoral delivery of vectors through the main excretory ducts. Existing studies suggest that clinical benefits will result from salivary gland targeted systemic gene therapeutics.

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“…For instance, the administration of an adenovirus encoding human growth hormone protein to the SG resulted in systemic protein expression. [2][3][4][5] More recently, we have demonstrated that systemic protein expression can also be obtained with nonviral DNA formulations. 6 Although administration of viral-based vectors to the SGs of experimental animals results in therapeutic concentrations of protein in blood, the recent complications that have occurred in clinical studies have increased concerns about the general safety of viral technologies.…”

Section: Introductionmentioning

confidence: 99%

Enhanced systemic transgene expression after nonviral salivary gland transfection using a novel endonuclease inhibitor/DNA formulation

Olson

et al. 2003

Gene Ther

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Gene transfer to the major salivary glands is an attractive method for the systemic delivery of therapeutic proteins. To date, nonviral gene transfer to these glands has resulted in inadequate systemic protein concentrations. We believe that identification of the barriers responsible for this inefficient transfection will enable the development of enhanced nonviral gene transfer in salivary glands and other tissues. One potential barrier is the degradation of plasmid DNA by endonucleases. To test this hypothesis, we coadministered two endonuclease inhibitors ((zinc and aurintricarboxylic acid (ATA)) with plasmid DNA, containing the secreted alkaline phosphatase gene (SEAP), to the submandibular glands of rats. The effect of zinc and ATA on SEAP expression, tissue accumulation of plasmid DNA, and plasmid DNA stability was then characterized. We observed that mixtures containing zinc/DNA, ATA/DNA, and zinc/ATA/DNA significantly enhanced both systemic transgene expression and the amount of plasmid DNA associated with treated tissues. The relative endonuclease inhibitory activity of zinc, ATA, and zinc/ATA correlated with the observed effects on transfection efficacy. The use of zinc/ATA enhanced the efficacy of salivary gland transfection by at least 1000-fold versus DNA alone. Importantly, this improved performance resulted in robust systemic secretion of an exogenous protein (SEAP), thus demonstrating the potential this nonviral gene transfer technology has as a method to treat systemic protein deficiencies.

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Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

Cited by 88 publications

References 22 publications

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

Utilizing endocrine secretory pathways in salivary glands for systemic gene therapeutics

Enhanced systemic transgene expression after nonviral salivary gland transfection using a novel endonuclease inhibitor/DNA formulation

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