Gene transfer into vascular cells

AbstractThe goal of gene therapy is to introduce foreign deoxyribonucleic acid (DNA) into somatic cells to correct or prevent disorders caused by the malfunction of genes within a diseased individual. Overexpression of recombinant genes at specific sites within the vasculature can provide insights into vascular biology and potential treatments for various cardiovascular disorders such as restenosis. Methods for the introduction of foreign DNA into endothelial and vascular smooth muscle cells have been developed recently. These include the genetic modification of endothelium in vitro and implantation in vivo on arterial segments, direct infection of the arterial wall in vivo with a replication-defective retroviral vector expressing a recombinant gene and direct transfer of genes into vascular cells in vivo with use of liposomes. Although still in its formative stages, gene transfer into the vasculature holds promise as a potential treatment for vascular diseases, including atherosclerosis and restenosis. This approach may also provide insight into the role of specific gene products in the development of pathologic lesions

Gene transfer and cardiovascular disease

Through the introduction of foreign DNA into somatic cells, the aim of gene therapy is to correct or prevent disorders caused by the absence or malfunction of genes within a diseased individual. Expression of recombinant genes at specific sites within the vasculature can provide insights into vascular biology and potential treatments for various cardiovascular disorders. In our studies, we have developed methods for the transfer of recombinant genes into the endothelium and vascular smooth muscle cells by using retroviral vectors and liposomal transfection. Although these techniques are still in the formative stages, gene transfer into the endothelium and other vascular cells is a new approach to the treatment of vascular diseases, including atherosclerosis and restenosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29517/1/0000604.pd

Evaluating two soil carbon models within the global land surface model JSBACH using surface and spaceborne observations of atmospheric CO₂

The trajectories of soil carbon (C) in the changing climate are of utmost importance, as soil carbon is a substantial carbon storage with a large potential to impact the atmospheric carbon dioxide (CO2) burden. Atmospheric CO2 observations integrate all processes affecting C exchange between the surface and the atmosphere. Therefore they provide a benchmark for carbon cycle models. We evaluated two distinct soil carbon models (CBALANCE and YASSO) that were implemented to a global land surface model (JSBACH) against atmospheric CO2 observations. We transported the biospheric carbon fluxes obtained by JSBACH using the atmospheric transport model TM5 to obtain atmospheric CO2. We then compared these results with surface observations from Global Atmosphere Watch (GAW) stations as well as with column XCO2 retrievals from the GOSAT satellite. The seasonal cycles of atmospheric CO2 estimated by the two different soil models differed. The estimates from the CBALANCE soil model were more in line with the surface observations at low latitudes (0 N–45 N) with only 1 % bias in the seasonal cycle amplitude (SCA), whereas YASSO was underestimating the SCA in this region by 32 %. YASSO gave more realistic seasonal cycle amplitudes of CO2 at northern boreal sites (north of 45 N) with underestimation of 15 % compared to 30 % overestimation by CBALANCE. Generally, the estimates from CBALANCE were more successful in capturing the seasonal patterns and seasonal cycle amplitudes of atmospheric CO2 even though it overestimated soil carbon stocks by 225 % (compared to underestimation of 36 % by YASSO) and its predictions of the global distribution of soil carbon stocks was unrealistic. The reasons for these differences in the results are related to the different environmental drivers and their functional dependencies of these two soil carbon models. In the tropical region the YASSO model showed earlier increase in season of the heterotophic respiration since it is driven by precipitation instead of soil moisture as CBALANCE. In the temperate and boreal region the role of temperature is more dominant. There the heterotophic respiration from the YASSO model had larger annual variability, driven by air temperature, compared to the CBALANCE which is driven by soil temperature. The results underline the importance of using sub-yearly data in the development of soil carbon models when they are used in shorter than annual time scales

Safety and Toxicity of Catheter Gene Delivery to the Pulmonary Vasculature in a Patient with Metastatic Melanoma

Overview summary Transcatheter delivery of HLA-B7 DNA and cationic liposomes into a segment of a pulmonary artery was safely performed in 1 patient with tumor nodules in the lung. No immunologic or organ toxicities were observed. Percutaneous catheter gene delivery has been performed in humans. Further refinements of this approach may lead to useful treatments for a variety of human diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63196/1/hum.1994.5.9-1089.pd

Analysis of the Copenhagen Accord pledges and its global climatic impacts‚ a snapshot of dissonant ambitions

This analysis of the Copenhagen Accord evaluates emission reduction pledges by individual countries against the Accord's climate-related objectives. Probabilistic estimates of the climatic consequences for a set of resulting multi-gas scenarios over the 21st century are calculated with a reduced complexity climate model, yielding global temperature increase and atmospheric CO2 and CO2-equivalent concentrations. Provisions for banked surplus emission allowances and credits from land use, land-use change and forestry are assessed and are shown to have the potential to lead to significant deterioration of the ambition levels implied by the pledges in 2020. This analysis demonstrates that the Copenhagen Accord and the pledges made under it represent a set of dissonant ambitions. The ambition level of the current pledges for 2020 and the lack of commonly agreed goals for 2050 place in peril the Accord's own ambition: to limit global warming to below 2 °C, and even more so for 1.5 °C, which is referenced in the Accord in association with potentially strengthening the long-term temperature goal in 2015. Due to the limited level of ambition by 2020, the ability to limit emissions afterwards to pathways consistent with either the 2 or 1.5 °C goal is likely to become less feasibl

A New Cationic Liposome DNA Complex Enhances the Efficiency of Arterial Gene Transfer In Vivo

Overview summary GAP-DLRIE/DOPE, a new cationic liposome preparation, is an efficient liposomal vector that increases gene expression in arteries compared to naked DNA or previously described cationic DNA–liposome complexes by more than 15-fold. Although less efficient than adenoviral gene transfer, these levels of gene expression represent a significant improvement in liposome transfection in vivo and approach levels observed with clinically acceptable doses of adenoviral vectors. The improvement in gene expression, together with the relative safety associated with liposomal gene transfer, suggests that such nonviral vectors may be appropriate for human gene therapy protocols which utilize catheter-based gene delivery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63105/1/hum.1996.7.15-1803.pd