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Research Update
RESEARCH UPDATE
doi:10.1016/mthe.2004.2491
Telomerase as a Weapon against HIV
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ew research has shown that constitutive expression of telomerase can prevent the premature aging of immune cells that fight HIV, thereby prolonging their defense against the infection. The research was published in the 15 November 2004 issue of the Journal of Immunology. Telomeres at the ends of chromosomes shorten progressively with each cell division, and can effectively limit the number of times a cell can divide. “Immune cells that fight HIV are under constant strain to divide in order to continue performing their protective functions. This massive amount of division shortens these cells’ telomeres prematurely,” explained author, Dr. Rita Effros. “So, the telomeres of a 40-year-old person infected with HIV resemble those of a healthy 90-year-old person.” Effros and first author Mirabelle Dagarag hypothesized that they might be able to exploit the activity of telomerase to provide a boost to AIDS patient’s exhausted immune systems. They extracted CD8+ immune cells from the blood of HIV-infected persons and engineered them to express the gene for human telomerase (hTERT) constitutively. They found that the engineered cells grew at a normal rate and did not exhibit any chromosomal abnormalities. “We also saw that telomerase stabilized the telomere length,” said Dagarag. “The telomere didn’t shorten each time the cell divided, which left the cell able to vigorously battle HIV much longer.” “To battle HIV infection effectively, we must strengthen the human immune system—not just suppress the virus as current drugs do,” said Effros. “We need a two-pronged approach to attack the disease from both sides of the medical equation.” Effros and the
MOLECULAR THERAPY Vol. 11, No. 1, January 2005 Copyright © The American Society of Gene Therapy
Geron Corporation, which collaborated on this study, are also testing several nongenetic methods of activating telomerase as potential treatments for persons infected with HIV. The Journal of Immunology, (2004), 173: 63036311. Doi not provided by publisher.
Lentivector Treats Mouse Model of Fabry Disease
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esearchers have tested a gene transfer approach that shows promise for early and sustained correction of a mouse model of Fabry disease, an inherited disorder whose sufferers have a reduced life expectancy. The study appears in the 15 November 2004 issue of the Proceedings of the National Academy of Sciences. Fabry disease is a lysosomal storage disorder that leads to the build-up of lipids in endothelial cells lining vessel walls, causing constriction, and leading eventually to cardiac disease, kidney disease or stroke. “Patients with Fabry disease either don’t make enough of the enzyme α-galactosidase A or improper synthesis means the enzyme isn’t active enough,” says author Jeffrey Medin. Medin and his colleagues demonstrated that an engineered lentiviral vector administered a day or two after birth can correct the defect long term in Fabry mice, ensuring they produce the appropriate enzyme at relevant levels. “Our previous strategies targeted genetic correction of the disease in adult animals, and hence, older patients, but a lot of times the organ problems in Fabry disease are already initiated by the time the projected treatment started,” says Medin. “A lot of Fabry patients also develop antibodies to the corrective gene product, so we decided we needed to come up with a better way to get around the immunity issue and administer treatment before the severe organ conse-
quences became irreparable.” Throughout a significant portion of their lives, the corrected Fabry mice showed a sustained level of enzyme production at approximately fifty per cent of that found in the blood of normal mice, with corresponding increases in enzyme activity and fat reduction in target organs. “Current thought indicates that approximately a five per cent level of normal enzyme activity is enough to correct the disorder,” says Medin. The Proceedings of the National Academy of Sciences, online edition, doi: 10.1073/pnas.0407572101.
New Director of FDA’s Office of Cellular, Tissue and Gene Therapies
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he FDA has announced that Dr. Edward Otto has been selected to be the Director of the Office of Cellular, Tissue and Gene Therapies within the agency’s Center for Biologic Evaluation and Research (CBER). The Office of Cellular, Tissue and Gene Therapies plays a crucial role in FDA’s regulation of emerging biologic medical technologies. Dr. Otto received his Ph.D. from the University of North CarolinaChapel Hill (UNC) in 1987, and then did post-doctoral work at both UNC and Duke University. He joined Genetic Therapy, Inc., (GTI) in 1992, where he played key management and product development roles, including the development of gene transfer vectors, monitoring gene transfer and xenotransplantation studies, and the preparation of a number of clinical studies. In 2002 Dr. Otto became Chief Operating Officer of Intronn, Inc., where he both helped lead business development efforts and worked on development of RNA trans-splicing technologies.
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doi:10.1016/mthe.2004.2491
Telomerase as a Weapon against HIV
N
ew research has shown that constitutive expression of telomerase can prevent the premature aging of immune cells that fight HIV, thereby prolonging their defense against the infection. The research was published in the 15 November 2004 issue of the Journal of Immunology. Telomeres at the ends of chromosomes shorten progressively with each cell division, and can effectively limit the number of times a cell can divide. “Immune cells that fight HIV are under constant strain to divide in order to continue performing their protective functions. This massive amount of division shortens these cells’ telomeres prematurely,” explained author, Dr. Rita Effros. “So, the telomeres of a 40-year-old person infected with HIV resemble those of a healthy 90-year-old person.” Effros and first author Mirabelle Dagarag hypothesized that they might be able to exploit the activity of telomerase to provide a boost to AIDS patient’s exhausted immune systems. They extracted CD8+ immune cells from the blood of HIV-infected persons and engineered them to express the gene for human telomerase (hTERT) constitutively. They found that the engineered cells grew at a normal rate and did not exhibit any chromosomal abnormalities. “We also saw that telomerase stabilized the telomere length,” said Dagarag. “The telomere didn’t shorten each time the cell divided, which left the cell able to vigorously battle HIV much longer.” “To battle HIV infection effectively, we must strengthen the human immune system—not just suppress the virus as current drugs do,” said Effros. “We need a two-pronged approach to attack the disease from both sides of the medical equation.” Effros and the
MOLECULAR THERAPY Vol. 11, No. 1, January 2005 Copyright © The American Society of Gene Therapy
Geron Corporation, which collaborated on this study, are also testing several nongenetic methods of activating telomerase as potential treatments for persons infected with HIV. The Journal of Immunology, (2004), 173: 63036311. Doi not provided by publisher.
Lentivector Treats Mouse Model of Fabry Disease
R
esearchers have tested a gene transfer approach that shows promise for early and sustained correction of a mouse model of Fabry disease, an inherited disorder whose sufferers have a reduced life expectancy. The study appears in the 15 November 2004 issue of the Proceedings of the National Academy of Sciences. Fabry disease is a lysosomal storage disorder that leads to the build-up of lipids in endothelial cells lining vessel walls, causing constriction, and leading eventually to cardiac disease, kidney disease or stroke. “Patients with Fabry disease either don’t make enough of the enzyme α-galactosidase A or improper synthesis means the enzyme isn’t active enough,” says author Jeffrey Medin. Medin and his colleagues demonstrated that an engineered lentiviral vector administered a day or two after birth can correct the defect long term in Fabry mice, ensuring they produce the appropriate enzyme at relevant levels. “Our previous strategies targeted genetic correction of the disease in adult animals, and hence, older patients, but a lot of times the organ problems in Fabry disease are already initiated by the time the projected treatment started,” says Medin. “A lot of Fabry patients also develop antibodies to the corrective gene product, so we decided we needed to come up with a better way to get around the immunity issue and administer treatment before the severe organ conse-
quences became irreparable.” Throughout a significant portion of their lives, the corrected Fabry mice showed a sustained level of enzyme production at approximately fifty per cent of that found in the blood of normal mice, with corresponding increases in enzyme activity and fat reduction in target organs. “Current thought indicates that approximately a five per cent level of normal enzyme activity is enough to correct the disorder,” says Medin. The Proceedings of the National Academy of Sciences, online edition, doi: 10.1073/pnas.0407572101.
New Director of FDA’s Office of Cellular, Tissue and Gene Therapies
T
he FDA has announced that Dr. Edward Otto has been selected to be the Director of the Office of Cellular, Tissue and Gene Therapies within the agency’s Center for Biologic Evaluation and Research (CBER). The Office of Cellular, Tissue and Gene Therapies plays a crucial role in FDA’s regulation of emerging biologic medical technologies. Dr. Otto received his Ph.D. from the University of North CarolinaChapel Hill (UNC) in 1987, and then did post-doctoral work at both UNC and Duke University. He joined Genetic Therapy, Inc., (GTI) in 1992, where he played key management and product development roles, including the development of gene transfer vectors, monitoring gene transfer and xenotransplantation studies, and the preparation of a number of clinical studies. In 2002 Dr. Otto became Chief Operating Officer of Intronn, Inc., where he both helped lead business development efforts and worked on development of RNA trans-splicing technologies.
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