Browsing by Subject "Genetic Therapy"
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Item Dr. Sonia Skarlatos-leader, colleague, and friend: from vascular biology to gene therapy and the Cardiovascular Cell Therapy research network(Mary Ann Liebert, 2013-11) March, Keith L.; Medicine, School of MedicineIt is indeed a daunting task to write a memorial essay, to be able to relate to others the essence of a life with great impact. I write in remembrance of Sonia Skarlatos, PhD, who died after a short and valiant fight with cancer, following a life lived as a unique leader in a long and ongoing fight against cardiovascular disease. I write both as a member of the Cardiovascular Cell Therapy Research network, which Sonia pioneered, and also as an individual scientist who has shared with Sonia a parallel evolution of professional interests. Perhaps the best light I can shine on her professional and personal excellence is through my own stories about Sonia and our interactions over the past 20 years. I hope and believe that these anecdotes will evoke special memories and will resonate with many scientists and colleagues of Dr. Skarlatos. I am sure that each will have their own memory of her distinctive warmth and thoughtfulness. She artfully mixed these traits with her deep scientific understanding and profound desire to help advance our present knowledge of science into a future realization of clinical improvements.Item Efficient in vivo catheter-based pericardial gene transfer mediated by adenoviral vectors(Wiley, 1999-01) March, K.L.; Woody, M.; Mehdi, K.; Zipes, D.P.; Brantly, M.; Trapnell, B.C.; Medicine, School of MedicineAdenoviral vectors are promising agents for a number of in vivo gene therapy applications including diseases of the heart and coronary vessels. Efficient intravascular gene transfer to specific sites has been achieved in occluded vessels, but otherwise is hampered by the effect of blood flow on localized vector uptake in the vessel wall. An alternative delivery approach to coronary arteries is the expression of diffusible gene products into the pericardial space surrounding the heart and coronary arteries. However, in vivo pericardial access is comparatively difficult and has been limited to surgical approaches. We hypothesized that efficient adenovirus-mediated gene expression in pericardial lining mesothelium could be achieved by transmyocardial vector delivery to the pericardium. To evaluate this concept, a hollow, helical-tipped penetrating catheter was used to deliver vector-containing fluid directly into the intrapericardial space. The catheter was introduced percutaneously in anesthetized mongrel dogs, advanced into the right ventricle, and the tip passed through the apical right ventricular myocardium under direct radiographic visualization until the open end of the catheter tip resided in the intrapericardial space. Adenoviral vectors expressing either nuclear-localizing beta-galactosidase, cytoplasmic luciferase, or secreted human alpha 1AT reporters (Av1nBg, Av1Lu, or Av1Aa, respectively) were instilled through the catheter into the intrapericardial space. Three days later the animals were sacrificed and reporter gene expression was evaluated in pericardium, epicardium, and multiple other tissues. In animals receiving Av1nBg, beta-galactosidase activity was evident in most of the pericardial lining endothelium, up to 100% in many areas. In animals receiving Av1Lu, luciferase reporter activity was abundant in pericardial tissues, but near-background levels were observed in other organs. In animals receiving Av1Aa, human alpha 1AT was abundant (16-29 mg/ml) in pericardial fluid, but was undetectable in serum. All animals tolerated the procedure well with no electrocardiographic changes and no clinical sequelae. These observations demonstrate highly efficient adenovirus vector delivery and gene transfer and expression in the pericardium and support the feasibility of localized gene therapy via catheter-based pericardial approaches. We suggest that the pericardial sac may serve as a sustained-release protein delivery system for the generation of desired gene products or their metabolites for diffusion into the epicardial region.Item Immunology of Gene and Cell Therapy(Elsevier, 2020-03-04) Markusic, David M.; Martino, Ashley T.; Porada, Christopher D.; VandenDriessche, Thierry; Pediatrics, School of MedicineItem Intraceullar trafficking of the adeno-associated virus 2(2001) Hansen, Jonathan JamesItem Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells(Impact Journals, LLC, 2015-02-20) Liu, Youhong; Chen, Lin; Gong, Zhicheng; Shen, Liangfang; Kao, Chinghai; Hock, Janet M.; Sun, Lunquan; Li, Xiong; Department of Urology, IU school of MedicineOncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future.Item Molecular Therapy: Flagship of a Strong Fleet of Journals(Elsevier, 2020-01-08) Herzog, Roland W.; Pediatrics, School of MedicineItem Systemic Vascular Transduction by Capsid Mutant Adeno-Associated Virus After Intravenous Injection(Mary Ann Liebert, 2015-11) Lipinski, Daniel M.; Reid, Chris A.; Boye, Sanford L.; Peterson, James J.; Qi, Xiaoping; Boye, Shannon E.; Boulton, Michael E.; Hauswirth, William W.; Department of Ophthalmology, IU School of MedicineThe ability to effectively deliver genetic material to vascular endothelial cells remains one of the greatest unmet challenges facing the development of gene therapies to prevent diseases with underlying vascular etiology, such as diabetes, atherosclerosis, and age-related macular degeneration. Herein, we assess the effectiveness of an rAAV2-based capsid mutant vector (Y272F, Y444F, Y500F, Y730F, T491V; termed QuadYF+TV) with strong endothelial cell tropism at transducing the vasculature after systemic administration. Intravenous injection of QuadYF+TV resulted in widespread transduction throughout the vasculature of several major organ systems, as assessed by in vivo bioluminescence imaging and postmortem histology. Robust transduction of lung tissue was observed in QuadYF+TV-injected mice, indicating a role for intravenous gene delivery in the treatment of chronic diseases presenting with pulmonary complications, such as α1-antitrypsin deficiency. The QuadYF+TV vector cross-reacted strongly with AAV2 neutralizing antibodies, however, indicating that a targeted delivery strategy may be required to maximize clinical translatability.