A novel gene delivery method transduces porcine pancreatic duct epithelial cells

Griffin, Michelle; Restrepo, Miguel; Haija, Marwa Abu El; Wallen, Tanner J.; Buchanan, Evan G.; Rokhlina, Tatiana; Chen, Y H; McCray, Paul B.; Davidson, Beverly L.; Divekar, Abhay; Uç, Aliye

doi:10.1038/gt.2013.62

Cited by 14 publications

(12 citation statements)

References 53 publications

(80 reference statements)

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“…Recent studies, using CFTR correctors, demonstrate proof of principal that restoration of secretion is possible 42–44 . Novel and minimally invasive gene manipulation techniques developed in animal models can be translated to humans 45 . Finally, cell based therapies and CRISPR/Cas9 technology explored in animal models of diabetes and pancreatic cancer 46–49 , may prove to be useful in CP.…”

Section: Exocrine Complications Of Chronic Pancreatitismentioning

confidence: 99%

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

et al. 2016

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A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology; (2) exocrine complications; (3) endocrine complications; and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator (CFTR) potentiators as possible treatments for CP were discussed. Importantly, the need for chronic pancreatitis endpoints and intermediate targets for future drug trials was emphasized.

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Section: Exocrine Complications Of Chronic Pancreatitismentioning

confidence: 99%

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

et al. 2016

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“…It will be interesting to test these strategies in CF pigs, where gene or cell delivery may be more challenging because of the preexisting mucus and inflammation. CF pigs are also an interesting model for testing viral CFTR gene delivery via the celiac artery into the pancreas, a technique that has been recently established in wild-type piglets (Griffin et al 2014).…”

Section: The Potential Role Of Dmd and Cf Pig Models For Evaluating Tmentioning

confidence: 99%

Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies

et al. 2015

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Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine.Keywords pig, disease model, Duchenne muscular dystrophy, cystic fibrosis, exon skipping, genome editing, CRISPR/Cas Genetically Engineered Pig Models of Human Monogenic DiseasesRare monogenic diseases are an attractive market for the pharmaceutical industry, since they provide-once the underlying mutation is identified-validated targets for drug development (Brinkman et al. 2006) or genetic treatment approaches (O'Connor and Crystal 2006). Development of drugs for these orphan diseases frequently has higher success rates and shorter times to approval and may-in spite of much smaller target patient populations-generate potential lifetime revenues comparable to nonorphan drugs (Fagnan et al. 2014). Currently the molecular etiology for more than half of the estimated 7,000 rare monogenic human diseases is known, and marked acceleration of disease gene discovery is expected from the dramatic improvements in DNA-sequencing technologies and associated analyses (Boycott et al. 2013). Model organisms are required to dissect the biological consequences of a particular mutation and to provide proof of concept for therapeutic intervention. The mouse is the most widely used model organism in mammalian genetics, and powerful platforms/networks for large-scale systematic mutagenesis and standardized phenotyping have been established (Bradley et al. 2012;Infrafrontier Consortium 2015). However, mutant mouse models do not always reflect the phenotypes of the corresponding human genetic diseases.Moreover, translation of findings in mouse models into clinical studies and applications may be difficult. Thus, large animal models mimicking human anatomy and physiology more closely are additionally needed. In this respect, the pig as a monogastri...

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“…Notably, systemic venous delivery of rAAV2/ 9 did not transduce the pancreas in newborn pigs. 143 We have also tested rAAV transduction of the pancreas in newborn ferrets. Because newborn ferrets are much smaller than piglets, celiac artery or umbilical artery cannulation is not feasible.…”

Section: Gene Transfer To the Pancreas Of Ferrets And Pigsmentioning

confidence: 99%

“…[139][140][141][142] A minimally invasive procedure to deliver rAAV to the pancreas via the celiac artery, the vessel that supplies major branches to the pancreas, was developed and tested in newborn pigs. 143 In this study, the celiac artery was used for vector delivery within 24 hr of birth and accessed via umbilical artery catheterization. One month after delivering 2 · 10 12 particles of rAAV9-EGFP through the celiac artery, reporter expression was found in pancreatic ducts, including the intercalated and intralobular ducts; these ducts express the highest levels of CFTR in pig and human pancreatic tissue.…”

Section: Gene Transfer To the Pancreas Of Ferrets And Pigsmentioning

confidence: 99%

Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy

Yan¹,

Stewart²,

Sinn³

et al. 2014

Human Gene Therapy Clinical Development

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Large animal models of genetic diseases are rapidly becoming integral to biomedical research as technologies to manipulate the mammalian genome improve. The creation of cystic fibrosis (CF) ferrets and pigs is an example of such progress in animal modeling, with the disease phenotypes in the ferret and pig models more reflective of human CF disease than mouse models. The ferret and pig CF models also provide unique opportunities to develop and assess the effectiveness of gene and cell therapies to treat affected organs. In this review, we examine the organ disease phenotypes in these new CF models and the opportunities to test gene therapies at various stages of disease progression in affected organs. We then discuss the progress in developing recombinant replication-defective adenoviral, adeno-associated viral, and lentiviral vectors to target genes to the lung and pancreas in ferrets and pigs, the two most affected organs in CF. Through this review, we hope to convey the potential of these new animal models for developing CF gene and cell therapies.

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A novel gene delivery method transduces porcine pancreatic duct epithelial cells

Cited by 14 publications

References 53 publications

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies

Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy

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