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ANTI-AGING
BIOMEDICINE.
HIGH TECH BIO-MEDICAL TECHNOLOGIES FOR DISEASE TREATMENT
AND LIFE EXTENSION.
EXPERIMENTAL AND CLINICAL DATA.
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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.
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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.
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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.
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