Mech Ageing Dev 2003 Feb;124(2):219-27.
A strategy for the ubiquitous overexpression of human catalase and CuZn superoxide dismutase genes in transgenic mice.
Chen X, Mele J, Giese H, Van Remmen H, Dolle ME, Steinhelper M, Richardson A, Vijg J.
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 78229, San Antonio, TX, USA.

In the present study, we generated transgenic mice that overexpress catalase or CuZn superoxide dismutase (CuZnSOD) in all tissues using large genomic DNA fragments. An 80 kb human genomic DNA, containing the 33 kb human CAT gene as well as the 41 kb of 5' and the 6 kb of 3' flanking regions, was obtained by screening a human P1 library and was used to produce transgenic mice Tg(CAT). Transgenic mice Tg(SOD1) were produced by a similar strategy using a 64 kb human genomic DNA containing the 10 kb human SOD1 gene and the 27 kb of both 5' and 3' flanking regions. Catalase mRNA levels were 2-6- fold higher and catalase activity levels were 2-4- fold higher in the various tissues of the hemizygous Tg(CAT) mice compared with wild type mice. The mRNA levels for CuZnSOD were 2-12- fold higher and the CuZnSOD activity levels were 2-5- fold higher in the hemizygous Tg(SOD1) mice compared with wild type mice. In summary, our study demonstrates that a strategy of using large genomic DNA containing either the entire human CAT or SOD1 gene with large flanking regions gives ubiquitous increased _expression of CuZnSOD and catalase. In addition, the _expression of catalase closely reflects the tissue specific pattern found in the endogenous gene. These transgenic mice will be useful in studying the role of oxidative stress/damage in aging and age-related pathologies.

J Gerontol A Biol Sci Med Sci 2000 Jan;55(1):B5-9.
Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice.
Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ.
Department of Pediatrics, University of California, San Francisco 94143-0546, USA.

Oxidative damage has been implicated in the aging process and in a number of degenerative diseases. To investigate the role of oxygen radicals in the aging process in mammals, the life spans of transgenic mice on a CD-1 background expressing increased levels of CuZn superoxide dismutase (CuZnSOD), the enzyme that metabolizes superoxide radicals, were determined. Homozygous transgenic mice with a two- to five-fold elevation of CuZnSOD in various tissues showed a slight reduction of life span, whereas hemizygous mice with a 15- to 3-fold increase of CuZnSOD showed no difference in life span from that of the nontransgenic littermate controls. The results suggest that constitutive and ubiquitous overexpression of CuZnSOD alone is not sufficient to extend the life spans of transgenic mice.

Curr Hematol Rep. 2003 Jul;2(4):348-55.
Gene therapy for the hemoglobin disorders.
Persons DA, Nienhuis AW.
St. Jude Children's Research Hospital, 332 North Lauderdale Drive, Memphis, TN 38105, USA.

The hematologic disorders of beta-thalassemia and sickle cell disease are the most prevalent of human genetic diseases. Although palliative therapies and curative stem cell transplantation therapy have been developed for these disorders, treatment still remains suboptimal and many patients suffer significant morbidity and early mortality. Therefore, development of a gene therapy approach has been sought for many years. Major progress in the globin gene therapy field has been achieved by several laboratories. Using lentiviral vectors to obtain high-level _expression of complex globin gene cassettes, therapeutic correction of several murine models of beta-thalassemia, and sickle cell disease was recently reported. This progress, coupled with developments in the ability to select and expand genetically modified stem cells in vivo, has advanced the possibility of gene therapy for the hemoglobin disorders in the near future. We review the developments in several areas that are critical for successful gene therapy of the hemoglobin disorders.