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    Terence R Flotte MD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPediatrics
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North, S1-340
    Worcester MA 01655
    Phone508-856-2107
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentMicrobiology and Physiological Systems

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentClinical Population Health Research

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

        Overview 
        Narrative

        Dr Flotte received his undergraduate degree in the biological sciences from the University of New Orleans in 1982, and his medical degree from the Louisiana State University School of Medicine in 1986. After serving his residency in pediatrics at Johns Hopkins University, he completed a pediatric pulmonary fellowshipa and postdoctoral training in molecular virology there in 1992.

        In 1995, Dr. Flotte and his colleagues at Johns Hopkins became the first to use adeno-associated virus, or AAV, as a vehicle to deliver corrective genes to targeted sites in the body, including the damaged airways of adults with cystic fibrosis.

        In 1996, Dr Flotte joined the faculty of the University of Florida and was appointed Associate Director of UF’s Powell Gene Therapy Center. In 2000, he was named Director of the Powell Center and founding Director of the newly established UF Genetics Institute, a cross-campus multidisciplinary unit encompassing gene therapy, human genetics, agricultural genetics and comparative genomics. In 2002, Flotte stepped down from these roles to accept the position of Chair of the Department of Pediatrics.

        An internationally known pioneer in human gene therapy, Flotte is currently investigating the use of gene therapy for genetic diseases that affect children, including cystic fibrosis, alpha-1 antitrypsin (AAT) deficiency, type I diabetes, and disorders of fatty acid oxidation. He is currently conducting Phase I trials with rAAV expressing alpha-1antitrypsin in AAT-deficient patients. He has also focused on the study of adeno-associated virus (AAV) vectors. Dr. Flotte's laboratory has also focused on the mechanisms of AAV persistence, since these represent the basis for a more profound understanding of the potential for long-term safe and effective gene therapy.

        Office of the Dean Website

        Research

        Recombinant adeno-associated virus (AAV) gene therapy vectors for, cystic fibrosis (CF), alpha-1-antitrypsin deficiency (AAT) and fatty oxidation disorders (FAO)

        adeno virusAAV is a non-pathogenic human parvovirus which is commonly isolated from the respiratory tract of humans (Figure 1A). AAV’s life cycle includes a unique mechanism for persistence in human cells by means of site-specific integration into a region of chromosome 19, the AAVS1 site (Figure 1B). In 1993, our group published the results of the first successful in vivo gene transfer with AAV. In that study, AAV vectors carrying the human CF transmembrane conductance regulator (CFTR) gene were delivered to the bronchial epithelium of rabbits. Efficient gene transfer was observed which persisted for over 6 months without any detectable toxicity. Subsequently, we studied AAV-CFTR gene transfer in rhesus macaques. Our studies in rhesus served two purposes: 1.We performed the primary toxicology study to justify beginning our phase I trial of AAV-CFTR administration in humans, and 2. we studied vector integration and persistence in vivo for the first time. Since then our laboratory has gone on to perform phase I clinical trials delivering AAV2 expressing the CFTR gene in CF patients. Much has been learned form the early trials including that paucity of AAV2 receptors on the luminal side of the airways and the weak promoter activity in early vectors. This limited the efficiency and efficacy of the viral vectors used in the early trials. To overcome this, the lab has designed a more robust expression cassette delivering a CFTR ‘mini’ gene and has determined that AAV1 is far superior to AAV2 at transducing airways. These new generation viral vectors for CF gene therapy are currently undergoing pre-clinical testing and will soon be tested in patients. Our laboratory has also pioneered phase I clinical studies using intra-muscular administration of rAAV2 as well as this more novel AAV1 serotype expressing the gene for alpha-1-antitrypsin (AAT) in AAT deficient patients. We are also developing hybrid rAAV-RNAi approaches to treat AAT deficient liver disease in which a toxic gain of function of the mutant protein contributes to the pathology. The laboratory is also involved in gene therapy for fatty oxidation disorders. Specifically we are developing gene delivery for the Acyl-CoA Dehydrogenases family enzymes that initiate the first step of the B-oxidation pathway.

        Current Studies in Cystic Fibrosis

        CFTR+/+Cystic fibrosis (CF), the most common lethal, single-gene disorder affecting Northern Europeans and North Americans, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a chloride channel and a regulator of other ion channels, and many aspects of the CF phenotype are directly related to ion channel abnormalities attributable to CFTR mutation. What remains less clear, however, is how CFTR mutation leads to persistent endobronchial infection with Pseudomonas aeruginosa and severe airway inflammation which are the hallmarks of the lung pathology in CF. One theory, which remains controversial, contends that CFTR mutation primes CF cells to release greater quantities of pro-inflammatory cytokines than non-CF cells. One line of evidence in support of this theory is a Pseudomonas agarose bead airway infection model, in which CFTR knockout mice demonstrate greater weight loss and mortality and higher levels of pro-inflammatory cytokines than control mice. One of the limitations of this model has been its technical complexity and a wide variability of responses among individual animals. Because of the need for a technically simpler mouse model for inflammatory lung disease in CF, our laboratory has recently developed a new approach based on Aspergillus fumigatus (Af) sensitization and challenge. This model reproduces certain key immunologic and pathologic aspects of allergic bronchopulmonary aspergillosis (ABPA) an inflammatory lung phenotype that is much more common in CF patients than in any other clinical context. In the animal model studies, CFTR knockout mice demonstrated up-regulated levels of IL4 prior to sensitization, and subsequent to sensitization developed a hyper-IgE response and markedly divergent cytokine expression (including increased IL13, IL4, IL2, IL10, and KC) as compared with non-CF. While this CFTR-dependent inflammatory phenotype is potentially very promising, it has raised more questions than it answered. In particular, the divergence of expression of cytokines that are predominantly produced within lymphocytes, macrophages and other non-epithelial cells raises the possibility of an important role of CFTR itself in non-epithelial cells. Therefore our lab is currently studying which cell types contribute primarily to the CF-dependent inflammatory lung disease phenotype in Aspergillus-sensitized CF mice? What pathways or other mechanisms might be aberrantly regulated in affected cells?

        Gene and RNAi Therapy for Alpha-1 Antitrypsin

        Protease - Induced Lung DamageAlpha-1 antitrypsin (AAT) is one of the primary circulating serum antiproteases in humans. It inhibits a variety of serine proteinases, with neutrophil elastase being one of the most physiologically important, as well as inhibiting a number of metallo-proteinases and other pro-inflammatory and pro-apoptotic molecules. AAT is normally produced within hepatocytes and macrophages, where hepatocyte-derived AAT forms the bulk of the physiologic reserve of AAT. Approximately 4% of the North American and Northern European populations possess at least one copy of a mutant allele, known as PI*Z, which results from a single amino acid substitution of Lys for Glu at position 342. In the homozygous state, this mutation leads to severe deficiency of AAT, and can result in two distinct pathologic states: a lung disease which is primarily due to the loss of antiprotease function, and a liver disease (present to a significant degree in only 10% of patients) which is due to a toxic gain of function of the Z-AAT mutant protein. The mutation of Z-AAT leads to the loss of a crucial salt-bridge in a beta sheet region of the protein, allowing for the insertion of the reactive loop of a neighboring AAT molecule in between the two beta sheets. The structure of the resultant very stable loop-sheet polymers has been solved and provides insight into how the mutant may accumulate in a misfolded configuration. This accumulation within hepatocytes consistently results in a state of serum deficiency due to inefficient secretion. In individuals affected by AAT liver disease, it also triggers a cascade of aberrant signals within the hepatocyte, most likely the result of an unfolded protein response. However, the downstream details remain unclear, as does the reason for the disparity between those Z-homozygotes who develop liver disease and those who do not. Regardless of the precise mechanism by which Z-AAT conformational changes lead to liver disease, there is general consensus that molecular therapies for AAT liver disease should act by down-regulating Z-AAT. Our group has developed two different investigational clinical gene therapy products for gene augmentation of AAT as a potential therapy for the lung disease (rAAV2-AAT and rAAV1-AAT) (1, 4), and we have a third vector in development that is much more efficient for delivery of wild-type (M) AAT to hepatocytes (rAAV8-AAT). Given the need for down-regulation of Z-AAT, we have also begun to examine a number of innovative approaches to long-term expression of therapeutic RNAs using the recombinant adeno-associated virus (rAAV) platform, including spliceosome-mediated RNA trans-splicing (SMaRT), and rAAV-mediated in vivo delivery of RNAi in Z-AAT transgenic mice, a project which was recently published from our laboratory. The constructs in that paper utilized a pol III promoter (U6) to express short hairpin RNAs (shRNAs) targeting three different sites on the AAT molecule, but were not specific to the mutant allele. While it is feasible to direct silencing agents to the liver to decrease Z-AAT expression, while directing gene augmentation to other sites, the hepatocyte is most likely the optimal target for augmentation as well. Our lab is currently focusing on systematically developing RNAi-based approaches to Z-AAT down-regulation within hepatocytes and to devise appropriate strategies that might allow this to be combined with M-AAT gene augmentation

        Gene Therapy for Fatty Oxidation Disorders

        Genetic disorders of mitochondrial fatty acid oxidation (FAO) represent a relatively common class of metabolic disorders, exceeding more than 1 in 15,000 newborns. These disorders are associated with genes involved in the mitochondrial b-oxidation of fatty acids, which provide fuel once glycogen stores are depleted during prolonged fasting or during times of increased energy demands and physiological stress. During these circumstances liberation from triglycleride stores in adipose tissue causes free fatty acids circulate to the liver and striated muscle. After the fatty acids diffuse (short chain) or are actively transported (long chain) across the cellular and mitochondrial membranes, the oxidation of fatty acids occurs within the mitochondrial matrix. b-oxidation proceeds in a cyclical fashion resulting in the removal of sequential 2-carbon units as acetyl-CoA, for entry into the TCA cycle

        Importantly, the first step of each cycle in the mitochondrial matrix is catalyzed by an acyl-CoA dehydrogenase. This rate limiting function is performed by a family of enzymes that differ in their substrate specificity based on the carbon chain length of the acyl CoA molecule. The acyl-CoA dehydrogenases (ACDs) are a family of 5 mitochondrial enzymes involved in fatty acid and amino acid metabolism that catalyze the transfer of electrons from various acyl-CoA esters to electron transfer flavoprotein. Very long, medium and short chain acyl-CoA dehydrogenases (VLCAD, MCAD and SCAD) catalyze the first step in the b-oxidation cycle with substrate specificities of 16-, 8- and 4- carbon chains, respectively.

        cytosolCurrently our lab is applying rAAV-based transduction of skeletal muscle for those FAO deficiencies that are most common in humans, medium chain acyl CoA dehydrogenase (MCAD) and very long chain acyl CoA dehydrodgenase (VLCAD). Over the past 5 years, mouse models have become available for each of these disorders, and mass newborn screening for FAO disorders has been initiated in many states. Our prior work has relied heavily on rAAV1 pseudotyped vectors for skeletal muscle transduction. The emergence of rAAV9-based vectors now provides the potential for even greater efficiency in using transduction of skeletal muscle and cardiac muscle as a platform for gene therapy of systemic genetic diseases. We are investigating to compare rAAV1 and rAAV9 in the context of a translational application to VLCAD and MCAD deficiencies. Specifically, the feasibility of molecular and biochemical correction of VLCAD and MCAD deficiencies is tested in mouse models of these deficiencies. Our primary focus is on determining whether rAAV9 (vs. rAAV1)-mediated transduction of skeletal and cardiac muscle will result in greater improvement of acyl carnitine profiles (i.e., clearance of abnormally high levels of fatty acyl carnitine metabolites that are characteristic of this disorder) and MRS profiles. We are also going to develop formal preclinical toxicology studies of muscle delivery of rAAV9 or rAAV1-VLCAD and rAAV9 or rAAV1-MCAD which will be completed in anticipation of new phase I clinical trials of gene therapy for these FAO disorders.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Kiem HP, Baum C, Bushman FD, Byrne BJ, Carter BJ, Cavagnaro J, Malech HL, Mendell JR, Naldini LM, Sorrentino BP, Williams DA, Flotte TR. Charting a Clear Path: The ASGCT Standardized Pathways Conference. Mol Ther. 2014 Jul; 22(7):1235-8.
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        2. Flotte TR, Mueller C. What is suppression of anti-adeno-associated virus capsid T-cells achieving? Hum Gene Ther. 2014 Mar; 25(3):178-9.
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        3. Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B, Sandhaus RA, McElvaney NG, Messina L, Tang Q, Rouhani FN, Campbell-Thompson M, Fu AD, Yachnis A, Knop DR, Ye GJ, Brantly M, Calcedo R, Somanathan S, Richman LP, Vonderheide RH, Hulme MA, Brusko TM, Wilson JM, Flotte TR. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest. 2013 Dec 2; 123(12):5310-8.
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        4. Flotte TR. Birth of a New Therapeutic Platform: 47 Years of Adeno-associated Virus Biology From Virus Discovery to Licensed Gene Therapy. Mol Ther. 2013 Nov; 21(11):1976-81.
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        5. Ahmed SS, Li H, Cao C, Sikoglu EM, Denninger AR, Su Q, Eaton S, Liso Navarro AA, Xie J, Szucs S, Zhang H, Moore C, Kirschner DA, Seyfried TN, Flotte TR, Matalon R, Gao G. A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice. Mol Ther. 2013 Dec; 21(12):2136-47.
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        6. Zhong L, Malani N, Li M, Brady T, Xie J, Bell P, Li S, Jones H, Wilson JM, Flotte TR, Bushman FD, Gao G. Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction. Hum Gene Ther. 2013 May; 24(5):520-5.
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        7. Mueller C, Flotte TR. Gene-based therapy for alpha-1 antitrypsin deficiency. COPD. 2013 Mar; 10 Suppl 1:44-9.
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        8. Tremblay JP, Xiao X, Aartsma-Rus A, Barbas C, Blau HM, Bogdanove AJ, Boycott K, Braun S, Breakefield XO, Bueren JA, Buschmann M, Byrne BJ, Calos M, Cathomen T, Chamberlain J, Chuah M, Cornetta K, Davies KE, Dickson JG, Duchateau P, Flotte TR, Gaudet D, Gersbach CA, Gilbert R, Glorioso J, Herzog RW, High KA, Huang W, Huard J, Joung JK, Liu D, Liu D, Lochmüller H, Lustig L, Martens J, Massie B, Mavilio F, Mendell JR, Nathwani A, Ponder K, Porteus M, Puymirat J, Samulski J, Takeda S, Thrasher A, VandenDriessche T, Wei Y, Wilson JM, Wilton SD, Wolfe JH, Gao G. Translating the genomics revolution: the need for an international gene therapy consortium for monogenic diseases. Mol Ther. 2013 Feb; 21(2):266-8.
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        9. Gruntman AM, Bish LT, Mueller C, Sweeney HL, Flotte TR, Gao G. Gene transfer in skeletal and cardiac muscle using recombinant adeno-associated virus. Curr Protoc Microbiol. 2013; Chapter 14:Unit 14D.3.
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        10. Bouchecareilh M, Hutt DM, Szajner P, Flotte TR, Balch WE. Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of a1-antitrypsin deficiency. J Biol Chem. 2012 Nov 2; 287(45):38265-78.
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        11. Bickford JS, Mueller C, Newsom KJ, Barilovits SJ, Beachy DE, Herlihy JD, Keeler B, Flotte TR, Nick HS. Effect of allergy and inflammation on eicosanoid gene expression in CFTR deficiency. J Cyst Fibros. 2013 May; 12(3):258-65.
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        12. Gruntman AM, Mueller C, Flotte TR, Gao G. Gene transfer in the lung using recombinant adeno-associated virus. Curr Protoc Microbiol. 2012 Aug; Chapter 14:Unit14D.2.
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        13. Keeler AM, Flotte TR. Cell and gene therapy for genetic diseases: inherited disorders affecting the lung and those mimicking sudden infant death syndrome. Hum Gene Ther. 2012 Jun; 23(6):548-56.
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        14. Lockett AD, Van Demark M, Gu Y, Schweitzer KS, Sigua N, Kamocki K, Fijalkowska I, Garrison J, Fisher AJ, Serban K, Wise RA, Flotte TR, Mueller C, Presson RG, Petrache HI, Tuder RM, Petrache I. Effect of cigarette smoke exposure and structural modifications on the a-1 Antitrypsin interaction with caspases. Mol Med. 2012; 18:445-54.
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        15. Keeler AM, Conlon T, Walter G, Zeng H, Shaffer SA, Dungtao F, Erger K, Cossette T, Tang Q, Mueller C, Flotte TR. Long-term correction of very long-chain acyl-coA dehydrogenase deficiency in mice using AAV9 gene therapy. Mol Ther. 2012 Jun; 20(6):1131-8.
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        16. Xie J, Ameres SL, Friedline R, Hung JH, Zhang Y, Xie Q, Zhong L, Su Q, He R, Li M, Li H, Mu X, Zhang H, Broderick JA, Kim JK, Weng Z, Flotte TR, Zamore PD, Gao G. Long-term, efficient inhibition of microRNA function in mice using rAAV vectors. Nat Methods. 2012 Apr; 9(4):403-9.
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        17. Bickford JS, Newsom KJ, Herlihy JD, Mueller C, Keeler B, Qiu X, Walters JN, Su N, Wallet SM, Flotte TR, Nick HS. Induction of group IVC phospholipase A2 in allergic asthma: transcriptional regulation by TNFa in bronchoepithelial cells. Biochem J. 2012 Feb 15; 442(1):127-37.
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        18. Mueller C, Tang Q, Gruntman A, Blomenkamp K, Teckman J, Song L, Zamore PD, Flotte TR. Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. Mol Ther. 2012 Mar; 20(3):590-600.
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        19. Ettinger WH, Flotte TR. The role of gene and cell therapy in the era of health care reform. Hum Gene Ther. 2011 Nov; 22(11):1307-9.
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        20. Marella M, Seo BB, Flotte TR, Matsuno-Yagi A, Yagi T. No immune responses by the expression of the yeast Ndi1 protein in rats. PLoS One. 2011; 6(10):e25910.
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        21. Flotte TR, Trapnell BC, Humphries M, Carey B, Calcedo R, Rouhani F, Campbell-Thompson M, Yachnis AT, Sandhaus RA, McElvaney NG, Mueller C, Messina LM, Wilson JM, Brantly M, Knop DR, Ye GJ, Chulay JD. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing a1-antitrypsin: interim results. Hum Gene Ther. 2011 Oct; 22(10):1239-47.
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        22. Flotte TR, Frederickson RM, Lowenstein PR, Mueller C. Moving forward toward a cure for Parkinson's: neuropathology of the nigrostriatal pathway determines the location of growth factor delivery. Mol Ther. 2011 May; 19(5):827-9.
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        23. Flotte TR, Mueller C. Gene therapy for alpha-1 antitrypsin deficiency. Hum Mol Genet. 2011 Apr 15; 20(R1):R87-92.
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        24. Chen KA, Cruz PE, Lanuto DJ, Flotte TR, Borchelt DR, Srivastava A, Zhang J, Steindler DA, Zheng T. Cellular fusion for gene delivery to SCA1 affected Purkinje neurons. Mol Cell Neurosci. 2011 May; 47(1):61-70.
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        25. Silver JN, Elder M, Conlon T, Cruz P, Wright AJ, Srivastava A, Flotte TR. Recombinant adeno-associated virus-mediated gene transfer for the potential therapy of adenosine deaminase-deficient severe combined immune deficiency. Hum Gene Ther. 2011 Aug; 22(8):935-49.
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        26. Flotte TR, Conlon TJ, Mueller C. Preclinical study design for rAAV. Methods Mol Biol. 2011; 807:317-37.
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        27. Xie J, Xie Q, Zhang H, Ameres SL, Hung JH, Su Q, He R, Mu X, Seher Ahmed S, Park S, Kato H, Li C, Mueller C, Mello CC, Weng Z, Flotte TR, Zamore PD, Gao G. MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression. Mol Ther. 2011 Mar; 19(3):526-35.
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        28. Chulay JD, Ye GJ, Thomas DL, Knop DR, Benson JM, Hutt JA, Wang G, Humphries M, Flotte TR. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum Gene Ther. 2011 Feb; 22(2):155-65.
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        29. Moore MJ, Flotte TR. Autoimmunity in a genetic disease—a cautionary tale. N Engl J Med. 2010 Oct 7; 363(15):1473-5.
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        30. Flotte TR. Sendai virus vectors. Pushing the envelope in the lung. Gene Ther. 2011 Feb; 18(2):107-8.
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        31. Lock M, McGorray S, Auricchio A, Ayuso E, Beecham EJ, Blouin-Tavel V, Bosch F, Bose M, Byrne BJ, Caton T, Chiorini JA, Chtarto A, Clark KR, Conlon T, Darmon C, Doria M, Douar A, Flotte TR, Francis JD, Francois A, Giacca M, Korn MT, Korytov I, Leon X, Leuchs B, Lux G, Melas C, Mizukami H, Moullier P, Müller M, Ozawa K, Philipsberg T, Poulard K, Raupp C, Rivière C, Roosendaal SD, Samulski RJ, Soltys SM, Surosky R, Tenenbaum L, Thomas DL, van Montfort B, Veres G, Wright JF, Xu Y, Zelenaia O, Zentilin L, Snyder RO. Characterization of a recombinant adeno-associated virus type 2 Reference Standard Material. Hum Gene Ther. 2010 Oct; 21(10):1273-85.
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        32. Mueller C, Braag SA, Keeler A, Hodges C, Drumm M, Flotte TR. Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. Am J Respir Cell Mol Biol. 2011 Jun; 44(6):922-9.
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        33. Martino AT, Mueller C, Braag S, Cruz PE, Campbell-Thompson M, Jin S, Flotte TR. N-glycosylation augmentation of the cystic fibrosis epithelium improves Pseudomonas aeruginosa clearance. Am J Respir Cell Mol Biol. 2011 Jun; 44(6):824-30.
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        34. Buff SM, Yu H, McCall JN, Caldwell SM, Ferkol TW, Flotte TR, Virella-Lowell IL. IL-10 delivery by AAV5 vector attenuates inflammation in mice with Pseudomonas pneumonia. Gene Ther. 2010 May; 17(5):567-76.
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        35. Mueller C, Keeler A, Braag S, Menz T, Tang Q, Flotte TR. Modulation of exaggerated-IgE allergic responses by gene transfer-mediated antagonism of IL-13 and IL-17e. Mol Ther. 2010 Mar; 18(3):511-8.
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        36. Mueller C, Strayer MS, Sirninger J, Braag S, Branco F, Louboutin JP, Flotte TR, Strayer DS. In vitro and in vivo functional characterization of gutless recombinant SV40-derived CFTR vectors. Gene Ther. 2010 Feb; 17(2):227-37.
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        37. Flotte TR, Fischer AC, Goetzmann J, Mueller C, Cebotaru L, Yan Z, Wang L, Wilson JM, Guggino WB, Engelhardt JF. Dual reporter comparative indexing of rAAV pseudotyped vectors in chimpanzee airway. Mol Ther. 2010 Mar; 18(3):594-600.
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        38. Stalvey MS, Flotte TR. Endocrine parameters of cystic fibrosis: back to basics. J Cell Biochem. 2009 Oct 1; 108(2):353-61.
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        39. Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M, Spencer LT, Rouhani F, Conlon TJ, Calcedo R, Betts MR, Spencer C, Byrne BJ, Wilson JM, Flotte TR. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci U S A. 2009 Sep 22; 106(38):16363-8.
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        40. Goel VK, Ibrahim N, Jiang G, Singhal M, Fee S, Flotte T, Westmoreland S, Haluska FS, Hinds PW, Haluska FG. Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene. 2009 Jun 11; 28(23):2289-98.
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        41. Pashuck TD, Franz SE, Altman MK, Wasserfall CH, Atkinson MA, Wronski TJ, Flotte TR, Stalvey MS. Murine model for cystic fibrosis bone disease demonstrates osteopenia and sex-related differences in bone formation. Pediatr Res. 2009 Mar; 65(3):311-6.
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        42. Yu H, Zeidan YH, Wu BX, Jenkins RW, Flotte TR, Hannun YA, Virella-Lowell I. Defective acid sphingomyelinase pathway with Pseudomonas aeruginosa infection in cystic fibrosis. Am J Respir Cell Mol Biol. 2009 Sep; 41(3):367-75.
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        43. Mueller C, Flotte TR. Gene therapy for cystic fibrosis. Clin Rev Allergy Immunol. 2008 Dec; 35(3):164-78.
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        44. Liqun Wang R, McLaughlin T, Cossette T, Tang Q, Foust K, Campbell-Thompson M, Martino A, Cruz P, Loiler S, Mueller C, Flotte TR. Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of alpha-1-antitrypsin using invasive and noninvasive delivery. Mol Ther. 2009 Jan; 17(1):81-7.
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        45. Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct; 19(10):979-90.
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        46. Beattie SG, Goetzman E, Tang Q, Conlon T, Campbell-Thompson M, Matern D, Vockley J, Flotte TR. Recombinant adeno-associated virus-mediated gene delivery of long chain acyl coenzyme A dehydrogenase (LCAD) into LCAD-deficient mice. J Gene Med. 2008 Oct; 10(10):1113-23.
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        47. Mueller C, Braag SA, Martino AT, Tang Q, Campbell-Thompson M, Flotte TR. The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr-/- -dependent allergy mouse model. Gene Ther. 2009 Feb; 16(2):172-83.
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        48. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang JJ, Sumaroka A, Windsor EA, Wilson JM, Flotte TR, Fishman GA, Heon E, Stone EM, Byrne BJ, Jacobson SG, Hauswirth WW. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008 Sep 30; 105(39):15112-7.
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        49. Stalvey MS, Brusko TM, Mueller C, Wasserfall CH, Schatz DA, Atkinson MA, Flotte TR. CFTR mutations impart elevated immune reactivity in a murine model of cystic fibrosis related diabetes. Cytokine. 2008 Oct; 44(1):154-9.
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        50. Flotte TR, Goetzmann J, Caridi J, Paolillo J, Conlon TJ, Potter M, Mueller C, Byrne BJ. Apparently nonspecific enzyme elevations after portal vein delivery of recombinant adeno-associated virus serotype 2 vector in hepatitis C virus-infected chimpanzees. Hum Gene Ther. 2008 Jul; 19(7):681-9.
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        51. Silver JN, Flotte TR. Towards a rAAV-based gene therapy for ADA-SCID: from ADA deficiency to current and future treatment strategies. Pharmacogenomics. 2008 Jul; 9(7):947-68.
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        52. Beattie SG, Goetzman E, Conlon T, Germain S, Walter G, Campbell-Thompson M, Matern D, Vockley J, Flotte TR. Biochemical correction of short-chain acyl-coenzyme A dehydrogenase deficiency after portal vein injection of rAAV8-SCAD. Hum Gene Ther. 2008 Jun; 19(6):579-88.
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        53. Cebotaru L, Vij N, Ciobanu I, Wright J, Flotte T, Guggino WB. Cystic fibrosis transmembrane regulator missing the first four transmembrane segments increases wild type and DeltaF508 processing. J Biol Chem. 2008 Aug 8; 283(32):21926-33.
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        54. Flotte TR. In utero efficacy of cystic fibrosis gene therapy: difficult studies, positive or negative. Mol Ther. 2008 May; 16(5):806-7.
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        55. Mueller C, Flotte TR. Clinical gene therapy using recombinant adeno-associated virus vectors. Gene Ther. 2008 Jun; 15(11):858-63.
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        56. Foust KD, Poirier A, Pacak CA, Mandel RJ, Flotte TR. Neonatal intraperitoneal or intravenous injections of recombinant adeno-associated virus type 8 transduce dorsal root ganglia and lower motor neurons. Hum Gene Ther. 2008 Jan; 19(1):61-70.
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        57. Mueller C, Torrez D, Braag S, Martino A, Clarke T, Campbell-Thompson M, Flotte TR. Partial correction of the CFTR-dependent ABPA mouse model with recombinant adeno-associated virus gene transfer of truncated CFTR gene. J Gene Med. 2008 Jan; 10(1):51-60.
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        58. Foust KD, Flotte TR, Reier PJ, Mandel RJ. Recombinant adeno-associated virus-mediated global anterograde delivery of glial cell line-derived neurotrophic factor to the spinal cord: comparison of rubrospinal and corticospinal tracts in the rat. Hum Gene Ther. 2008 Jan; 19(1):71-82.
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        61. Cruz PE, Mueller C, Flotte TR. The promise of gene therapy for the treatment of alpha-1 antitrypsin deficiency. Pharmacogenomics. 2007 Sep; 8(9):1191-8.
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        62. Cruz PE, Mueller C, Cossette TL, Golant A, Tang Q, Beattie SG, Brantly M, Campbell-Thompson M, Blomenkamp KS, Teckman JH, Flotte TR. In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Invest. 2007 Sep; 87(9):893-902.
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        63. Erger KE, Conlon TJ, Leal NA, Zori R, Bobik TA, Flotte TR. In vivo expression of human ATP:cob(I)alamin adenosyltransferase (ATR) using recombinant adeno-associated virus (rAAV) serotypes 2 and 8. J Gene Med. 2007 Jun; 9(6):462-9.
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        64. Chen B, Kapturczak MH, Joseph R, George JF, Campbell-Thompson M, Wasserfall CH, Atkinson MA, Tisher CC, Flotte TR, Agarwal A, Chen S. Adeno-associated viral vector-mediated interleukin-10 prolongs allograft survival in a rat kidney transplantation model. Am J Transplant. 2007 May; 7(5):1112-20.
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        65. Flotte TR, Conlon TJ, Poirier A, Campbell-Thompson M, Byrne BJ. Preclinical characterization of a recombinant adeno-associated virus type 1-pseudotyped vector demonstrates dose-dependent injection site inflammation and dissemination of vector genomes to distant sites. Hum Gene Ther. 2007 Mar; 18(3):245-56.
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        66. Fischer AC, Smith CI, Cebotaru L, Zhang X, Askin FB, Wright J, Guggino SE, Adams RJ, Flotte T, Guggino WB. Expression of a truncated cystic fibrosis transmembrane conductance regulator with an AAV5-pseudotyped vector in primates. Mol Ther. 2007 Apr; 15(4):756-63.
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        67. Flotte TR, Ng P, Dylla DE, McCray PB, Wang G, Kolls JK, Hu J. Viral vector-mediated and cell-based therapies for treatment of cystic fibrosis. Mol Ther. 2007 Feb; 15(2):229-41.
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        68. Brantly ML, Spencer LT, Humphries M, Conlon TJ, Spencer CT, Poirier A, Garlington W, Baker D, Song S, Berns KI, Muzyczka N, Snyder RO, Byrne BJ, Flotte TR. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther. 2006 Dec; 17(12):1177-86.
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        69. Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, Petrache HI, Flotte TR, Tuder RM. alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol. 2006 Oct; 169(4):1155-66.
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        70. Flotte TR, Frentzen B, Humphries MR, Rosenbloom AL. Recent developments in the protection of pediatric research subjects. J Pediatr. 2006 Sep; 149(3):285-286.
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        71. Milligan ED, Sloane EM, Langer SJ, Hughes TS, Jekich BM, Frank MG, Mahoney JH, Levkoff LH, Maier SF, Cruz PE, Flotte TR, Johnson KW, Mahoney MM, Chavez RA, Leinwand LA, Watkins LR. Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain. 2006 Dec 15; 126(1-3):294-308.
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        72. Blenman KR, Duan B, Xu Z, Wan S, Atkinson MA, Flotte TR, Croker BP, Morel L. IL-10 regulation of lupus in the NZM2410 murine model. Lab Invest. 2006 Nov; 86(11):1136-48.
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        73. Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY, Sumaroka A, Pearce-Kelling SE, Aguirre GD, Kaushal S, Maguire AM, Flotte TR, Hauswirth WW. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther. 2006 Aug; 17(8):845-58.
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        74. Stalvey MS, Muller C, Schatz DA, Wasserfall CH, Campbell-Thompson ML, Theriaque DW, Flotte TR, Atkinson MA. Cystic fibrosis transmembrane conductance regulator deficiency exacerbates islet cell dysfunction after beta-cell injury. Diabetes. 2006 Jul; 55(7):1939-45.
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        75. Lu Y, Choi YK, Campbell-Thompson M, Li C, Tang Q, Crawford JM, Flotte TR, Song S. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J Gene Med. 2006 Jun; 8(6):730-5.
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        76. Jacobson SG, Acland GM, Aguirre GD, Aleman TS, Schwartz SB, Cideciyan AV, Zeiss CJ, Komaromy AM, Kaushal S, Roman AJ, Windsor EA, Sumaroka A, Pearce-Kelling SE, Conlon TJ, Chiodo VA, Boye SL, Flotte TR, Maguire AM, Bennett J, Hauswirth WW. Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther. 2006 Jun; 13(6):1074-84.
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        77. Seo BB, Nakamaru-Ogiso E, Flotte TR, Matsuno-Yagi A, Yagi T. In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease. J Biol Chem. 2006 May 19; 281(20):14250-5.
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        78. Petrache I, Fijalkowska I, Zhen L, Medler TR, Brown E, Cruz P, Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Shapiro L, Zhang B, Song S, Hicklin D, Voelkel NF, Flotte T, Tuder RM. A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med. 2006 Jun 1; 173(11):1222-8.
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        79. Müller C, Braag SA, Herlihy JD, Wasserfall CH, Chesrown SE, Nick HS, Atkinson MA, Flotte TR. Enhanced IgE allergic response to Aspergillus fumigatus in CFTR-/- mice. Lab Invest. 2006 Feb; 86(2):130-40.
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        80. Kaplan KA, Beierle EA, Faro A, Eskin TA, Flotte TR. Recurrent pneumonia in children: a case report and approach to diagnosis. Clin Pediatr (Phila). 2006 Jan-Feb; 45(1):15-22.
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        81. Conlon TJ, Walter G, Owen R, Cossette T, Erger K, Gutierrez G, Goetzman E, Matern D, Vockley J, Flotte TR. Systemic correction of a fatty acid oxidation defect by intramuscular injection of a recombinant adeno-associated virus vector. Hum Gene Ther. 2006 Jan; 17(1):71-80.
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        82. Flotte TR. Adeno-associated virus-based gene therapy for inherited disorders. Pediatr Res. 2005 Dec; 58(6):1143-7.
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        83. Loiler SA, Tang Q, Clarke T, Campbell-Thompson ML, Chiodo V, Hauswirth W, Cruz P, Perret-Gentil M, Atkinson MA, Ramiya VK, Flotte TR. Localized gene expression following administration of adeno-associated viral vectors via pancreatic ducts. Mol Ther. 2005 Sep; 12(3):519-27.
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        84. Swiatecka-Urban A, Brown A, Moreau-Marquis S, Renuka J, Coutermarsh B, Barnaby R, Karlson KH, Flotte TR, Fukuda M, Langford GM, Stanton BA. The short apical membrane half-life of rescued {Delta}F508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of {Delta}F508-CFTR in polarized human airway epithelial cells. J Biol Chem. 2005 Nov 4; 280(44):36762-72.
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        85. Conlon TJ, Cossette T, Erger K, Choi YK, Clarke T, Scott-Jorgensen M, Song S, Campbell-Thompson M, Crawford J, Flotte TR. Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector. Mol Ther. 2005 Nov; 12(5):867-75.
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        86. Flotte TR, Schwiebert EM, Zeitlin PL, Carter BJ, Guggino WB. Correlation between DNA transfer and cystic fibrosis airway epithelial cell correction after recombinant adeno-associated virus serotype 2 gene therapy. Hum Gene Ther. 2005 Aug; 16(8):921-8.
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        87. Virella-Lowell I, Zusman B, Foust K, Loiler S, Conlon T, Song S, Chesnut KA, Ferkol T, Flotte TR. Enhancing rAAV vector expression in the lung. J Gene Med. 2005 Jul; 7(7):842-50.
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        92. Milligan ED, Sloane EM, Langer SJ, Cruz PE, Chacur M, Spataro L, Wieseler-Frank J, Hammack SE, Maier SF, Flotte TR, Forsayeth JR, Leinwand LA, Chavez R, Watkins LR. Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10. Mol Pain. 2005; 1:9.
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        93. Chen S, Kapturczak M, Loiler SA, Zolotukhin S, Glushakova OY, Madsen KM, Samulski RJ, Hauswirth WW, Campbell-Thompson M, Berns KI, Flotte TR, Atkinson MA, Tisher CC, Agarwal A. Efficient transduction of vascular endothelial cells with recombinant adeno-associated virus serotype 1 and 5 vectors. Hum Gene Ther. 2005 Feb; 16(2):235-47.
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        94. Mohiuddin I, Loiler S, Zolotukhin I, Byrne BJ, Flotte TR, Snyder RO. Herpesvirus-based infectious titering of recombinant adeno-associated viral vectors. Mol Ther. 2005 Feb; 11(2):320-6.
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        95. Song S, Witek RP, Lu Y, Choi YK, Zheng D, Jorgensen M, Li C, Flotte TR, Petersen BE. Ex vivo transduced liver progenitor cells as a platform for gene therapy in mice. Hepatology. 2004 Oct; 40(4):918-24.
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        96. Virella-Lowell I, Herlihy JD, Liu B, Lopez C, Cruz P, Muller C, Baker HV, Flotte TR. Effects of CFTR, interleukin-10, and Pseudomonas aeruginosa on gene expression profiles in a CF bronchial epithelial cell Line. Mol Ther. 2004 Sep; 10(3):562-73.
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        97. Sirninger J, Muller C, Braag S, Tang Q, Yue H, Detrisac C, Ferkol T, Guggino WB, Flotte TR. Functional characterization of a recombinant adeno-associated virus 5-pseudotyped cystic fibrosis transmembrane conductance regulator vector. Hum Gene Ther. 2004 Sep; 15(9):832-41.
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        99. Flotte TR. Immune responses to recombinant adeno-associated virus vectors: putting preclinical findings into perspective. Hum Gene Ther. 2004 Jul; 15(7):716-7.
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        102. Bray CL, Cahill KS, Oshier JT, Peden CS, Theriaque DW, Flotte TR, Stacpoole PW. Methylphenidate does not improve cognitive function in healthy sleep-deprived young adults. J Investig Med. 2004 Apr; 52(3):192-201.
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        103. Song S, Lu Y, Choi YK, Han Y, Tang Q, Zhao G, Berns KI, Flotte TR. DNA-dependent PK inhibits adeno-associated virus DNA integration. Proc Natl Acad Sci U S A. 2004 Feb 17; 101(7):2112-6.
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        104. Zhang YC, Powers M, Wasserfall C, Brusko T, Song S, Flotte T, Snyder RO, Potter M, Scott-Jorgensen M, Campbell-Thompson M, Crawford JM, Nick HS, Agarwal A, Ellis TM, Atkinson MA. Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity. Gene Ther. 2004 Feb; 11(3):233-40.
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        105. Song S, Goudy K, Campbell-Thompson M, Wasserfall C, Scott-Jorgensen M, Wang J, Tang Q, Crawford JM, Ellis TM, Atkinson MA, Flotte TR. Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice. Gene Ther. 2004 Jan; 11(2):181-6.
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        106. Flotte TR, Brantly ML, Spencer LT, Byrne BJ, Spencer CT, Baker DJ, Humphries M. Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum Gene Ther. 2004 Jan; 15(1):93-128.
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        107. Fischer AC, Beck SE, Smith CI, Laube BL, Askin FB, Guggino SE, Adams RJ, Flotte TR, Guggino WB. Successful transgene expression with serial doses of aerosolized rAAV2 vectors in rhesus macaques. Mol Ther. 2003 Dec; 8(6):918-26.
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        108. Burkhardt BR, Loiler SA, Anderson JA, Kilberg MS, Crawford JM, Flotte TR, Goudy KS, Ellis TM, Atkinson M. Glucose-responsive expression of the human insulin promoter in HepG2 human hepatoma cells. Ann N Y Acad Sci. 2003 Nov; 1005:237-41.
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        109. Loiler SA, Conlon TJ, Song S, Tang Q, Warrington KH, Agarwal A, Kapturczak M, Li C, Ricordi C, Atkinson MA, Muzyczka N, Flotte TR. Targeting recombinant adeno-associated virus vectors to enhance gene transfer to pancreatic islets and liver. Gene Ther. 2003 Sep; 10(18):1551-8.
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        110. Goudy KS, Burkhardt BR, Wasserfall C, Song S, Campbell-Thompson ML, Brusko T, Powers MA, Clare-Salzler MJ, Sobel ES, Ellis TM, Flotte TR, Atkinson MA. Systemic overexpression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. J Immunol. 2003 Sep 1; 171(5):2270-8.
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        111. Flotte TR, Zeitlin PL, Reynolds TC, Heald AE, Pedersen P, Beck S, Conrad CK, Brass-Ernst L, Humphries M, Sullivan K, Wetzel R, Taylor G, Carter BJ, Guggino WB. Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum Gene Ther. 2003 Jul 20; 14(11):1079-88.
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        112. Stacpoole PW, Owen R, Flotte TR. The pyruvate dehydrogenase complex as a target for gene therapy. Curr Gene Ther. 2003 Jun; 3(3):239-45.
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        113. Flotte TR. The signal and the trap: targeted delivery and retention of proteins in the mitochondrion. Mol Ther. 2003 Jun; 7(6):715-6.
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        115. Zhang YC, Pileggi A, Agarwal A, Molano RD, Powers M, Brusko T, Wasserfall C, Goudy K, Zahr E, Poggioli R, Scott-Jorgensen M, Campbell-Thompson M, Crawford JM, Nick H, Flotte T, Ellis TM, Ricordi C, Inverardi L, Atkinson MA. Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice. Diabetes. 2003 Mar; 52(3):708-16.
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        116. Barbour KW, Wei F, Brannan C, Flotte TR, Baumann H, Berger FG. The murine alpha(1)-proteinase inhibitor gene family: polymorphism, chromosomal location, and structure. Genomics. 2002 Nov; 80(5):515-22.
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        117. Zhang YC, Molano RD, Pileggi A, Powers M, Cross J, Wasserfall C, Scott-Jorgensen M, Campbell-Thompson M, Crawford JM, Flotte T, Ellis TM, Ricordi C, Atkinson MA, Inverardi L. Adeno-associated virus transduction of islets with interleukin-4 results in impaired metabolic function in syngeneic marginal islet mass transplantation. Transplantation. 2002 Oct 27; 74(8):1184-6.
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        119. Beck SE, Laube BL, Barberena CI, Fischer AC, Adams RJ, Chesnut K, Flotte TR, Guggino WB. Deposition and expression of aerosolized rAAV vectors in the lungs of Rhesus macaques. Mol Ther. 2002 Oct; 6(4):546-54.
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        120. Owen R, Mandel RJ, Ammini CV, Conlon TJ, Kerr DS, Stacpoole PW, Flotte TR. Gene therapy for pyruvate dehydrogenase E1alpha deficiency using recombinant adeno-associated virus 2 (rAAV2) vectors. Mol Ther. 2002 Sep; 6(3):394-9.
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        121. Seo BB, Nakamaru-Ogiso E, Flotte TR, Yagi T, Matsuno-Yagi A. A single-subunit NADH-quinone oxidoreductase renders resistance to mammalian nerve cells against complex I inhibition. Mol Ther. 2002 Sep; 6(3):336-41.
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        122. Song S, Scott-Jorgensen M, Wang J, Poirier A, Crawford J, Campbell-Thompson M, Flotte TR. Intramuscular administration of recombinant adeno-associated virus 2 alpha-1 antitrypsin (rAAV-SERPINA1) vectors in a nonhuman primate model: safety and immunologic aspects. Mol Ther. 2002 Sep; 6(3):329-35.
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        123. Wagner JA, Nepomuceno IB, Messner AH, Moran ML, Batson EP, Dimiceli S, Brown BW, Desch JK, Norbash AM, Conrad CK, Guggino WB, Flotte TR, Wine JJ, Carter BJ, Reynolds TC, Moss RB, Gardner P. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum Gene Ther. 2002 Jul 20; 13(11):1349-59.
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        124. Mah C, Fraites TJ, Zolotukhin I, Song S, Flotte TR, Dobson J, Batich C, Byrne BJ. Improved method of recombinant AAV2 delivery for systemic targeted gene therapy. Mol Ther. 2002 Jul; 6(1):106-12.
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        125. Flotte TR. Recombinant adeno-associated virus gene therapy for cystic fibrosis and alpha(1)-antitrypsin deficiency. Chest. 2002 Mar; 121(3 Suppl):98S-102S.
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        131. Donsante A, Vogler C, Muzyczka N, Crawford JM, Barker J, Flotte T, Campbell-Thompson M, Daly T, Sands MS. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther. 2001 Sep; 8(17):1343-6.
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        132. Song S, Embury J, Laipis PJ, Berns KI, Crawford JM, Flotte TR. Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther. 2001 Sep; 8(17):1299-306.
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        133. Flotte TR, Laube BL. Gene therapy in cystic fibrosis. Chest. 2001 Sep; 120(3 Suppl):124S-131S.
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        134. Owen R, Flotte TR. Approaches and limitations to gene therapy for mitochondrial diseases. Antioxid Redox Signal. 2001 Jun; 3(3):451-60.
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        136. Xu L, Daly T, Gao C, Flotte TR, Song S, Byrne BJ, Sands MS, Parker Ponder K. CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum Gene Ther. 2001 Mar 20; 12(5):563-73.
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        137. Song S, Laipis PJ, Berns KI, Flotte TR. Effect of DNA-dependent protein kinase on the molecular fate of the rAAV2 genome in skeletal muscle. Proc Natl Acad Sci U S A. 2001 Mar 27; 98(7):4084-8.
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        139. Stacpoole PW, Fisher WR, Flotte TR, Geiser EA, Theriaque DW, Hutson AD. Teaching hypothesis-oriented thinking to medical students: the University of Florida's clinical investigation program. Acad Med. 2001 Mar; 76(3):287-92.
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        140. Seo BB, Wang J, Flotte TR, Yagi T, Matsuno-Yagi A. Use of the NADH-quinone oxidoreductase (NDI1) gene of Saccharomyces cerevisiae as a possible cure for complex I defects in human cells. J Biol Chem. 2000 Dec 1; 275(48):37774-8.
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        141. Fishbein L, O'Brien P, Hutson A, Theriaque D, Stacpoole PW, Flotte T. Pharmacokinetics and pharmacodynamic effects of nicotine nasal spray devices on cardiovascular and pulmonary function. J Investig Med. 2000 Nov; 48(6):435-40.
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        144. Wu P, Xiao W, Conlon T, Hughes J, Agbandje-McKenna M, Ferkol T, Flotte T, Muzyczka N. Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism. J Virol. 2000 Sep; 74(18):8635-47.
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        147. Hernandez YJ, Wang J, Kearns WG, Loiler S, Poirier A, Flotte TR. Latent adeno-associated virus infection elicits humoral but not cell-mediated immune responses in a nonhuman primate model. J Virol. 1999 Oct; 73(10):8549-58.
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        153. Wagner JA, Moran ML, Messner AH, Daifuku R, Conrad CK, Reynolds T, Guggino WB, Moss RB, Carter BJ, Wine JJ, Flotte TR, Gardner P. A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis. Hum Gene Ther. 1998 Apr 10; 9(6):889-909.
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        154. Flotte TR, Beck SE, Chesnut K, Potter M, Poirier A, Zolotukhin S. A fluorescence video-endoscopy technique for detection of gene transfer and expression. Gene Ther. 1998 Feb; 5(2):166-73.
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        155. Flotte TR, Carter BJ. Adeno-associated virus vectors for gene therapy of cystic fibrosis. Methods Enzymol. 1998; 292:717-32.
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        156. Rubenstein RC, McVeigh U, Flotte TR, Guggino WB, Zeitlin PL. CFTR gene transduction in neonatal rabbits using an adeno-associated virus (AAV) vector. Gene Ther. 1997 May; 4(5):384-92.
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        157. Flotte TR, Ferkol TW. Genetic therapy. Past, present, and future. Pediatr Clin North Am. 1997 Feb; 44(1):153-78.
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        158. Flotte TR, Carter BJ. In vivo gene therapy with adeno-associated virus vectors for cystic fibrosis. Adv Pharmacol. 1997; 40:85-101.
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        159. Kearns WG, Afione SA, Fulmer SB, Pang MC, Erikson D, Egan M, Landrum MJ, Flotte TR, Cutting GR. Recombinant adeno-associated virus (AAV-CFTR) vectors do not integrate in a site-specific fashion in an immortalized epithelial cell line. Gene Ther. 1996 Sep; 3(9):748-55.
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        160. Conrad CK, Allen SS, Afione SA, Reynolds TC, Beck SE, Fee-Maki M, Barrazza-Ortiz X, Adams R, Askin FB, Carter BJ, Guggino WB, Flotte TR. Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Ther. 1996 Aug; 3(8):658-68.
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        161. Baudard M, Flotte TR, Aran JM, Thierry AR, Pastan I, Pang MG, Kearns WG, Gottesman MM. Expression of the human multidrug resistance and glucocerebrosidase cDNAs from adeno-associated vectors: efficient promoter activity of AAV sequences and in vivo delivery via liposomes. Hum Gene Ther. 1996 Jul 10; 7(11):1309-22.
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        162. Flotte T, Carter B, Conrad C, Guggino W, Reynolds T, Rosenstein B, Taylor G, Walden S, Wetzel R. A phase I study of an adeno-associated virus-CFTR gene vector in adult CF patients with mild lung disease. Hum Gene Ther. 1996 Jun 10; 7(9):1145-59.
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        163. Afione SA, Conrad CK, Kearns WG, Chunduru S, Adams R, Reynolds TC, Guggino WB, Cutting GR, Carter BJ, Flotte TR. In vivo model of adeno-associated virus vector persistence and rescue. J Virol. 1996 May; 70(5):3235-41.
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        164. Carter BJ, Flotte TR. Development of adeno-associated virus vectors for gene therapy of cystic fibrosis. Curr Top Microbiol Immunol. 1996; 218:119-44.
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        165. Zeitlin PL, Chu S, Conrad C, McVeigh U, Ferguson K, Flotte TR, Guggino WB. Alveolar stem cell transduction by an adeno-associated viral vector. Gene Ther. 1995 Nov; 2(9):623-31.
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        166. Flotte TR, Carter BJ. Adeno-associated virus vectors for gene therapy. Gene Ther. 1995 Aug; 2(6):357-62.
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        167. Murray CB, Morales MM, Flotte TR, McGrath-Morrow SA, Guggino WB, Zeitlin PL. CIC-2: a developmentally dependent chloride channel expressed in the fetal lung and downregulated after birth. Am J Respir Cell Mol Biol. 1995 Jun; 12(6):597-604.
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        168. Carroll TP, Morales MM, Fulmer SB, Allen SS, Flotte TR, Cutting GR, Guggino WB. Alternate translation initiation codons can create functional forms of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1995 May 19; 270(20):11941-6.
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        169. Afione SA, Conrad CK, Flotte TR. Gene therapy vectors as drug delivery systems. Clin Pharmacokinet. 1995 Mar; 28(3):181-9.
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        170. Iinuma S, Bachor R, Flotte T, Hasan T. Biodistribution and phototoxicity of 5-aminolevulinic acid-induced PpIX in an orthotopic rat bladder tumor model. J Urol. 1995 Mar; 153(3 Pt 1):802-6.
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        171. Flotte TR, Barraza-Ortiz X, Solow R, Afione SA, Carter BJ, Guggino WB. An improved system for packaging recombinant adeno-associated virus vectors capable of in vivo transduction. Gene Ther. 1995 Jan; 2(1):29-37.
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        172. Flotte TR, Afione SA, Zeitlin PL. Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am J Respir Cell Mol Biol. 1994 Nov; 11(5):517-21.
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        173. Schwiebert EM, Flotte T, Cutting GR, Guggino WB. Both CFTR and outwardly rectifying chloride channels contribute to cAMP-stimulated whole cell chloride currents. Am J Physiol. 1994 May; 266(5 Pt 1):C1464-77.
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        174. Flotte TR, Afione SA, Conrad C, McGrath SA, Solow R, Oka H, Zeitlin PL, Guggino WB, Carter BJ. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Natl Acad Sci U S A. 1993 Nov 15; 90(22):10613-7.
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        175. Tomares SM, Flotte TR, Tunkel DE, Pao M, Loughlin GM. Real time laryngoscopy with olfactory challenge for diagnosis of psychogenic stridor. Pediatr Pulmonol. 1993 Oct; 16(4):259-62.
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        176. Roider J, Michaud N, Flotte T, Birngruber R. [Histology of retinal lesions after continuous irradiation and selective micro-coagulation of the retinal pigment epithelium]. Ophthalmologe. 1993 Jun; 90(3):274-8.
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        177. Flotte TR, Afione SA, Solow R, Drumm ML, Markakis D, Guggino WB, Zeitlin PL, Carter BJ. Expression of the cystic fibrosis transmembrane conductance regulator from a novel adeno-associated virus promoter. J Biol Chem. 1993 Feb 15; 268(5):3781-90.
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        178. Flotte TR. Prospects for virus-based gene therapy for cystic fibrosis. J Bioenerg Biomembr. 1993 Feb; 25(1):37-42.
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        179. Kochevar IE, Moran M, Lyon N, Flotte T, Siebert E, Gange RW. Effects of systemic indomethacin, meclizine, and BW755C on chronic ultraviolet B-induced effects in hairless mouse skin. J Invest Dermatol. 1993 Feb; 100(2):186-93.
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        180. Flotte TR, Solow R, Owens RA, Afione S, Zeitlin PL, Carter BJ. Gene expression from adeno-associated virus vectors in airway epithelial cells. Am J Respir Cell Mol Biol. 1992 Sep; 7(3):349-56.
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        181. Egan M, Flotte T, Afione S, Solow R, Zeitlin PL, Carter BJ, Guggino WB. Defective regulation of outwardly rectifying Cl- channels by protein kinase A corrected by insertion of CFTR. Nature. 1992 Aug 13; 358(6387):581-4.
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        182. Flotte TR, Loughlin GM. Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol. 1991; 10(3):178-82.
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        183. Flotte TR. Dietl syndrome: intermittent ureteropelvic junction obstruction as a cause of episodic abdominal pain. Pediatrics. 1988 Nov; 82(5):792-4.
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