Gene and cell based therapies

Delivery of gene transfer systems of heat shock proteins (Hsp70),250 antioxidant enzymes (catalase)251 or survival genes (Akt)252 has been associated with myocardial protection against ischemia and reperfusion. A vector gene therapy system has also been developed with a hypoxia response element-incorporated promoter to turn on the gene expression in response to hypoxic signal.253 

Cardiac cell therapy consists of transplanting cells into the infarcted area of the myocardium to increase or preserve the number of cardiomyocytes, improve vascular supply and increase contractile function. There are different types of regenerating cells with the capacity to proliferate and differentiate into functional cardiomyocytes. These include embryonic stem cells and adult stem cells. 

Studies using embryonic stem cells (ES) have shown cell maturation, successful engraftment, and an improvement of myocardial function. However, there are also certain drawbacks. ES are allogenic and immunosuppressive therapy might be needed, they are susceptible to ischemia and human ES may have the potential to form teratomas when injected into immunocompromized mouse, reviewed by Davani.254 

Adult stem cells include skeletal myoblasts and bone marrow stem cells. Skeletal myoblasts are highly resistant to ischemia, they are harvested as autologous cells and differentiate efficiently into adult skeletal muscle after transplantation. Electromechanical coupling between mature skeletal grafts and cardiac muscle has yet to be demonstrated. Furthermore, arrhythmias are reported to occur with the use of skeletal myoblasts.255 

It is now suggested that the adult heart may not be a terminally differentiated organ because it contains stem cells supporting its regeneration. Adult cardiac stem cells are multipotent, giving rise to endothelial cells, smooth muscle cells and functional cardiomyocytes. The existence of these cells opens new opportunities for myocardial repair.259 See chapter 6. 

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Melo LG, Pachori AS, Kong D, Gnecchi M. Gene and cell-based therapies for heart disease, FASEBJ2004 18 648-663,... 

Gene and Cell-based Therapies for Cardiovascular Disease... 

IV. Gene- and Cell-Based Therapies for Lung Cancer... 

Indeed, these experiments have led to Phase I clinical trials targeting malignant mesothelioma with both gene- and cell-based therapy (123), with the initial reports citing low toxicity and molecular evidence for in situ gene transfer (124,125). 

Batia R, Sharma S, Dubinett S. New gene and cell-based therapies for lung cancer. Semin Respir Med 2000 21 463-473. 

Although pharmacology still relies heavily on small chemical substances, biologicals like recombinant proteins, cell-based therapies, and gene-therapy approaches have great potential for the treatment of broad spectrum of diseases. Therefore, the focus of modem pharmacology should shift towards these innovative therapies. 

Volume II, Embryonic and Adult Stem Cells, provides an analysis of various types of stem cells and their therapeutic potential. It concentrates particularly on embryonic and neural stem cells. This volume covers the broader potential of adult stem cells its biology, significance and potential for therapy. This volume also describes the potential of stem cells for autologous transplantation, the stem cell theory of carcinogenesis, particularly the existence of brain tumor stem cells, and the therapeutic potential of gene therapy for cell-based therapy. 

Viral vector and cell-based vaccines FDA guidance for industry guidance for human somatic cell therapy and gene therapy 1998... 

Another strategy to treat tumors by stimulation of the immune system is to use cell-based therapies [86]. In addition to several therapies based on cytotoxic T-cells (e.g., adoptive T-cell therapy [87] or tumor-loaded, activated DCs [88]), one important approach is the use of gene-modified tumor cells. Cell-based tumor therapies can be divided into either autologous and allo-genous strategies ... 

Artificial enzymes for sequence-selective RNA scission are also important. If only one RNA can be selected from mar others in cells and is cleaved at the desired site, this shoirld open the way to new RNA science. Regulation of the expression of a specific gene in cells, advanced therapy, and RNA manipirlation are promising. However, none of the naturally occrrrring ri-bonucleases shows such a high sequence-selectivity. The so-called ribozymes are well suited for these purposes (Cech et al., 1981). However, these semi-artificial enzymes, based on RNA framework, do not necessarily fulfill all the requirements for versatile applications. The following factors sometimes impose limitations ... 

Coutu DL, Yousefi AM, Galipeau J. Three-dimensional porous scaffolds at the crossroads of tissue engineering and cell-based gene therapy. / Cell Biochem 2009 108 537-46. 

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