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Studies in Progress:

Stem Cells

Characterization of the biological properties of adult stromal cells is essential for a better understanding of their normal function in adults as well as to revealing their potential in treating disease. Stem cells are so named because they are like the stems on a tree that can produce new leaves and flowers each year. Each stem cells has the remarkable property that is can divide so as to produce a perfect copy of itself together with a second cell that can become a "workhorse" cell of the body such as a bone cell or a nerve cell. Because the stem cell produced by the division is a perfect copy of the original stem cell, stem cells seem to be able to divide and live indefinitely, perhaps forever. Understanding stem cells is now one of the most important problems of biology. The Center staff is working at the forefront of research on stem cells using cutting edge technologies to define them in terms of the genes they express. Also, they have developed new procedures that make it possible to begin with a small sample of stem cells from a patient's bone marrow and grow extremely large numbers of the cells in the laboratory. The ability to grow the cells rapidly, in turn, makes it possible to gene engineer the cells with simple techniques that do not involve use of a virus.

To test the cell's potentials for therapy of patients, the Center is using the adult stromal stem cells to treat mice and rats that represent models of human diseases. Plans are being made to carry out similar experiments in non-human primates at the nearby Tulane University Primate Center, the largest N. I. H. sponsored primate center in the country. In one series of experiments, cells are transplanted into mice that undergo repeated spontaneous bone fractures because of a genetic defect. The aim of these experiments is to determine if the stem cells can travel to the site of a bone fracture and strengthen the bone and prevent further fractures. Results from these studies should define the most effective ways the cells can be used to treat human bone diseases, such as osteogenesis imperfecta and osteoporosis. In other experiments, the Center staff is pursuing their discovery that the adult stem cells can differentiate into cells that make up the brain. Therefore, the cells are being transplanted directly into the brains of mice that exhibit progressive neurodegeneration due to lack of a critical protein. The aim of these experiments is to determine if the stem cells can replace the missing protein and reverse the degeneration of the brain. If the experiments succeed, they will suggest that the cells can be used to treat serious neurological diseases in children such as Tay-Sachs disease. Other studies are evaluating if the stem cells can replace brain cells lost in common diseases of adults. Promising preliminary results were recently obtained in a rat model for parkinsonism. Similar experiments are underway to test the effectiveness of the cells in animal models for Alzheimer's disease and brain tumors (gliomas). The procedures for the experiments in animal models are being developed so as to conform to reporting requirements of the Food and Drug Administration and other agencies in order that the therapies can be introduced as clinical trials in patients as soon as possible

Genetic Deficiencies

Another major interest of the Center is to identify the genetic causes of both common and diseases of connective tissues such as bone and cartilage. The Center staff was among the first to show that mutations in collagen genes can carry mutations causing diseases of bone and cartilage. Their interest in collagen genes was based on a large background of work they and others had done on the structure and function of the proteins and their biosynthesis. Members of the Center staff and their previous associates isolated the first gene for a series of human collagens. They then used the genes to find mutations that caused osteogenesis imperfecta and severe disorders of cartilage that cause dwarfism and associated problems (Stickler syndrome, spondyloepiphyseal dysplasia, and achondrogenesis type II, Kniest dysplasia). They went on to find mutations in collagen genes that caused the defects in a subset of patients with osteoporosis, a subset of patients with early onset osteoarthritis, and a subset of patients with aortic aneurisms that were prone to rupture. The Center found mutations in collagen genes that cause or predispose sciatica because of intervertebral disk herniation. The genes in which these mutations have been found are complex and the identification of the mutations has in part depended on technology developed by the Center staff for rapid scanning of genes for mutations, a technology known as conformation sensitive gel electrophoresis (CSGE). The DNA diagnostic tests for these and other diseases are being developed for several reasons. One is that a definitive diagnosis as to cause of a disease is frequently an important guide as to which existing therapies or changes in expectations or lifestyle may help the patient. The second reason is that knowing the exact cause of a disease is frequently the first step in developing new therapies, such as gene therapy, that may provide a cure for previously untreatable diseases.