Karen Rice

Telethon Institute of Genetics and Medicine, Napoli, Campania, Italy

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Publications (12)74.41 Total impact

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    ABSTRACT: Helper-dependent adenoviral vectors (HDAd) have been shown to mediate considerably longer duration of transgene expression compared to first generation adenoviral vectors. We have previously shown that transgene expression from HDAd transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effect. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3 to 111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment prior to clinical application of HDAd.
    Human gene therapy 07/2013; · 4.20 Impact Factor
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    ABSTRACT: Hemophilia B is an excellent candidate for gene therapy because low levels of factor IX (FIX) (≥1%) result in clinically significant improvement of the bleeding diathesis. Helper-dependent adenoviral (HDAd) vectors can mediate long-term transgene expression without chronic toxicity. To determine the potential for HDAd-mediated liver-directed hemophilia B gene therapy, we administered an HDAd expressing hFIX into rhesus macaques through a novel and minimally invasive balloon occlusion catheter-based method that permits preferential, high-efficiency hepatocyte transduction with low, subtoxic vector doses. Animals given 1 × 10(12) and 1 × 10(11) virus particle (vp)/kg achieved therapeutic hFIX levels for the entire observation period (up to 1,029 days). At 3 × 10(10) and 1 × 10(10) vp/kg, only subtherapeutic hFIX levels were achieved which were not sustained long-term. Balloon occlusion administration of HDAd was well tolerated with negligible toxicity. Five of six animals developed inhibitors to hFIX. These results provide important information in assessing the clinical utility of HDAd for hemophilia B gene therapy.
    Molecular Therapy 07/2012; 20(10):1863-70. · 7.04 Impact Factor
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    ABSTRACT: Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vector's therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy.
    Molecular Therapy 01/2009; 17(2):327-33. · 7.04 Impact Factor
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    ABSTRACT: Endothelial dysfunction signals the initiation and progression of atherosclerosis. Elevated LDL-cholesterol concentrations have been suggested to induce endothelial dysfunction, but direct in vivo evidence for the relation is still lacking. We examined the hypothesis that a high-cholesterol, high-fat (HCHF) diet can directly cause endothelial dysfunction in vivo. We measured inflammatory and endothelial dysfunctional markers in circulating blood and directly in endothelial cells, which were collected by femoral artery biopsies, in 10 baboons before and after a 7-wk HCHF dietary challenge. We found that the HCHF diet induced a high inflammatory status, as indicated by increased concentrations of interleukin 6, tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant protein 1. Although the concentrations of endothelial dysfunctional markers, such as soluble vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1, were not increased by the HCHF diet, membrane-bound VCAM-1 and membrane-bound E-selectin on endothelial cells were highly increased after 7 wk of the HCHF diet (P < 0.01). In contrast, the concentrations of endothelial nitric oxide synthase in endothelial cells were significantly reduced by the 7-wk HCHF diet (P < 0.01). Furthermore, the dietary challenge attenuated endothelial cell responses to TNF-alpha, lipopolysaccharide, native LDL cholesterol, and oxidized LDL-cholesterol stimulation. Our results show that an HCHF diet can directly induce inflammation and endothelial dysfunction. Prior in vivo exposure to an HCHF diet attenuates the in vitro responses of endothelial cells to atherogenic risk factors. This preconditioning phenomenon may have significant clinical relevance.
    American Journal of Clinical Nutrition 10/2005; 82(4):751-9. · 6.50 Impact Factor
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    ABSTRACT: Molecular Therapy (2005) 11, S317|[ndash]|S317; doi: 10.1016/j.ymthe.2005.07.352 815. Aerosol Delivery of Helper-Dependent Adenoviral Vector into Nonhuman Primate Lungs Results in High Efficiency Pulmonary Transduction with Minimal Toxicity Peter Hiatt1, Nicola Brunetti-Pierri2, David Koehler3, Ruth McConnell1, Julie Katkin1, Donna Palmer2, David Dimmock2, Jim Hu3, Milton Finegold4, Arthur Beaudet2, Dee Carey5, Karen Rice5 and Philip Ng21Pediatrics Pulmonary, Baylor College of Medicine, Houston, TX2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX3Programme in Lung Biology Research and the Canadian Institutes of Health Research Group in Lung Development, Hospital for Sick Children, Toronto, ON, Canada4Department of Pathology, Baylor College of Medicine, Houston, TX5Southwest Foundation for Biomedical Research, San Antonio, TX
    Molecular Therapy 04/2005; · 7.04 Impact Factor
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    ABSTRACT: Studies have shown that after controlling for the effects of body size on brain size, the brains of adult humans, rhesus monkeys, and chimpanzees differ in relative size, where males have a greater volume of cerebral tissue than females. We assess whether head circumference sexual dimorphism is present during early development by evaluating sex differences in relative head circumference in living fetuses and infants within the first year of life. Head circumference is used as a proxy for brain size in the fetus and infant. Femur length is used as a proxy for body length in the fetus. Ultrasonography was used to obtain fetal measures, and anthropometry was used to obtain postnatal measures in humans, rhesus monkeys, baboons, and common marmosets. We show that statistically significant but low levels of head circumference sexual dimorphism are present in humans, rhesus monkeys, and baboons in early life. On average, males have head circumferences about 2% larger than females of comparable femur/body length in humans, rhesus monkeys, and baboons. No evidence for head circumference sexual dimorphism in the common marmoset was found. Dimorphism was present across all body size ranges. We suggest that head circumference sexual dimorphism emerges largely postnatally and increases throughout maturation, particularly in humans who reach adult dimorphism values greater than the monkeys. We suggest that brain dimorphism is not likely to impose an additional energetic burden to the gestating or lactating mother. Finally, some of the problems with ascribing functional significance to brain size sexual dimorphism are discussed, and the energetic implications for brain size sexual dimorphism in infancy are assessed.
    American Journal of Physical Anthropology 02/2005; 126(1):97-110. · 2.48 Impact Factor
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    ABSTRACT: Helper-dependent adenoviral vectors (HDAd) are attractive vectors for liver-directed gene therapy because they can mediate sustained, high level transgene expression with no long-term toxicity. However, as a consequence of a threshold effect, high vector doses are required to achieve efficient hepatic transduction by peripheral intravenous injection which unfortunately results in a dose-dependent activation of the innate inflammatory response. Clearly strategies to overcome the threshold to efficient hepatic transduction are needed to improve the therapeutic index of HDAd. We have recently shown that systemic hydrodynamic injection of HDAd into mice resulted in exceedingly high levels of hepatic transduction and reduction in both systemic vector dissemination and acute proinflammatory cytokines compared to conventional injection. Hydrodynamic injection offers a method of dramatically increasing the therapeutic index of HDAd but, unfortunately, cannot be applied to larger animals due to the large injection volume. Therefore, we have developed a minimally invasive method to mimic hydrodynamic injection in nonhuman primates which does not require injection of large volumes. This method involves the use of balloon occlusion catheters percutaneously positioned in the vena cava to transiently obstruct hepatic venous outflow to increase the intrahepatic pressure prior to simple peripheral intravenous injection of HDAd in a small volume. We demonstrate in nonhuman primates that this novel method of vector delivery results in an exceedingly high and unprecedented level of hepatic transduction with low vector doses resulting in stable, long-term transgene expression. This was accompanied by reduced systemic vector dissemination and minimal, transient elevations of proinflammatory cytokines. Despite the relatively high intrahepatic pressures achieved, there was minimal evidence of liver injury; no histological abnormalities were observed and only minimal and transient elevation of AST and ALT were noted. The procedure itself was uneventful and very well tolerated with no clinical manifestations of acute or chronic toxicities. This novel method of delivering HDAd is simple, minimally invasive, and clinically relevant since it increases the therapeutic index of HDAd for liver-directed gene therapy by allowing high efficiency hepatic transduction with low vector doses and with negligible acute or chronic toxicities.
    Molecular Therapy 01/2005; 11. · 7.04 Impact Factor
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    ABSTRACT: Helper-dependent adenoviral vectors (HDAd) are attractive vectors for liver-directed gene therapy because they can mediate sustained, high level transgene expression with negligible long-term toxicity. However, high vector doses are required to achieve efficient hepatic transduction by peripheral intravenous injection due to a nonlinear dose response. Unfortunately, such high systemic doses result in wide spread vector dissemination and dose-dependent activation of the acute inflammatory response which can result in severe and lethal acute toxicity. We hypothesize that this problem can be surmounted by delivering the vector exclusively to the liver thereby permitting high efficiency hepatic transduction with low vector doses and with minimal systemic vector dissemination. To test this hypothesis, we injected HDAd directly into the surgically isolated liver via the portal vein in nonhuman primates. Total hepatic isolation was achieved by occluding hepatic blood inflow from the portal vein and hepatic artery and by occluding hepatic blood outflow at the vena cava. Prior to total hepatic isolation, saline was infused into the portal vein to flush blood out of the liver. The vector was then injected directly into the isolated liver via the portal vein and allowed to dwell for 30 min to prolong exposure to hepatocytes. Following the 30 min dwell time, unabsorbed vector was removed from the liver to minimize systemic dissemination. This was accomplished by infusing saline into the portal vein and collecting the unabsorbed vector from a vena cava catheter. We investigated the safety, feasibility and efficacy of this approach and our results revealed that the surgical procedure was well tolerated in nonhuman primates and that significantly higher hepatic transduction efficiencies can be achieved with relatively low vector doses as compared to those obtained by peripheral intravenous injection. This approach may increase the safety and efficacy of HDAd-mediated, liver-directed gene therapy by minimizing the dose required to achieve efficient hepatic transduction and by minimizing systemic vector dissemination.
    Molecular Therapy 01/2004; 9. · 7.04 Impact Factor
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    ABSTRACT: Leptin gene expression is higher in females than in males, and is regulated by many factors including energy intake and insulin, but little is known about the inheritance of leptin gene expression. We have investigated leptin (LEP) gene express-ion, to determine whether it is heritable, and whether the difference in LEP expression between males and females has a genetic component. A total of 319 baboons (Papio hamadryas) (220 females, 99 males) from a captive, pedigreed colony. We cloned a baboon LEP cDNA, and quantified LEP mRNA expression in baboon omental adipose tissue using a ribonuclease protection assay. In addition, we assayed circulating leptin levels, adipocyte cell volume, and weight. We used maximum likelihood-based variance decomposition methods to determine the genetic architecture of LEP levels, including testing for genotype-by-sex interaction. Omental LEP mRNA expression was significantly and positively correlated with weight and adipocyte cell volume in baboons. Both mRNA and plasma levels of leptin were higher in females than in males, and both measures were heritable. The results of our genetic analysis show that there was a genotype-by-sex interaction in the levels of plasma leptin, but not in omental LEP mRNA. As in humans, baboon leptin mRNA and protein levels are expressed at a higher level in females than in males. We detected evidence that the plasma levels were affected by genes that are differentially expressed in males and females, while the omental mRNA levels were not. This finding suggests that the genes that differentially regulate plasma leptin levels between males and females may exert their effects on post-transcriptional processes.
    International Journal of Obesity 08/2003; 27(7):778-83. · 5.22 Impact Factor
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    ABSTRACT: The effects of intravenous administration of a first-generation adenoviral vector expressing beta-galactosidase were compared in two baboons receiving a high dose or lower dose of vector, 1.2 x 10(13) or 1.2 x 10(12) particles/kg, respectively. The high-dose baboon developed acute symptoms, decreased platelet counts, and increased liver enzymes, and became moribund at 48 hr after injection, while the lower-dose baboon developed no symptoms. Expression of the beta-galactosidase transgene was prominent in liver, spleen, and endothelium of the arterial vasculature in the high-dose baboon, but was much more limited and spared the endothelium in the lower-dose baboon. Injury to the vascular endothelium was the most prominent abnormality in the high-dose baboon. Extensive histological studies provide a detailed picture of the pathology associated with a lethal dose of first-generation adenoviral vector in a primate.
    Human Gene Therapy 02/2002; 13(1):143-54. · 4.02 Impact Factor
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    ABSTRACT: The development of improved gene transfer vectors has been hampered by the lack of a nonimmunogenic reporter gene that can be serially quantified in the serum or from other sites. In response to the need to develop a new reporter protein, we have evaluated alpha-fetoprotein (AFP) as a potential candidate. A first-generation E1/E3-deleted adenoviral vector expressing human AFP (hAFP) was generated as a preliminary tool to evaluate AFP as a reporter. Using both mouse and baboon models, hAFP expression was evaluated in serum after intravenous delivery and in serum and bronchioalveolar lavage (BAL) fluid after delivery to the lung. In immunocompetent animals, intravenous delivery of the hAFP adenoviral vector resulted in hAFP expression in the serum early after injection, which declined rapidly over time. Disappearance of hAFP from the serum was complete by 3-4 weeks after administration and was accompanied by robust antibody responses to hAFP and loss of infected cells. After lung delivery, hAFP could be detected in both serum and BAL. This allowed the analysis of the kinetics of gene expression in the lung without sacrificing the animals. In both liver and lung, immunohistochemical analysis correlated well with hAFP levels as detected in serum or BAL, indicating that serum levels were a reliable marker of tissue expression. Preliminary results with a mouse AFP expressed in a helper-dependent adenoviral vector indicate that use of a species-specific version of AFP will eliminate the complication of antibody development. These initial evaluations suggest that AFP is useful as a reporter gene to evaluate gene expression of therapeutic cassettes in multiple tissues, and it should be considered for use in human subjects.
    Molecular Therapy 01/2001; · 7.04 Impact Factor
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    ABSTRACT: The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human α1-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report, we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first-generation vectors expressing hAAT. Transgene expression was limited to approximately 3–5 months with the first-generation vectors. In contrast, administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of vectors of different serotypes.
    Proceedings of the National Academy of Sciences 10/1999; 96(22):12816-12821. · 9.74 Impact Factor

Publication Stats

462 Citations
44 Downloads
529 Views
74.41 Total Impact Points

Institutions

  • 2013
    • Telethon Institute of Genetics and Medicine
      Napoli, Campania, Italy
  • 2012
    • Texas Biomedical Research Institute
      San Antonio, Texas, United States
  • 2009–2012
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
  • 1999–2005
    • Southwest Foundation For Biomedical Research
      San Antonio, Texas, United States