PHILADELPHIA -- For the first time, researchers have successfully used gene therapy to treat a disease that affects organs throughout the body of a large animal. The results will be reported this week on the Web site of the Proceedings of the National Academy of Sciences. The study, led by Mark E. Haskins of the University of Pennsylvania School of Veterinary Medicine and Katherine Parker Ponder of Washington University School of Medicine in St. Louis, involved dogs with a rare disorder in which an enzyme deficiency causes clouding of the corneas, cardiac disease and bone abnormalities leading to loss of mobility by six months of age. Newborn dogs treated with hepatic gene therapy maintained near-normal mobility throughout the 17-month study and showed little evidence of the other debilitating signs normally associated with the disease.
"While gene therapy has been used previously in dogs, this is the first use to treat a disorder affecting multiple organ systems throughout the body," said Haskins, professor of pathology and medical genetics at Penn. "Previous applications of gene therapy in dogs have targeted disorders affecting a single bodily function, such as vision or blood clotting. Like many diseases that we might eventually like to treat with gene therapy, this one has complex, multisystemic effects."
The experiments involved seven dogs with mucopolysaccharidosis VII, a disorder in which the enzyme beta-glucuronidase is deficient in activity. Also known as Sly syndrome, MPS VII is among a constellation of lysosomal storage diseases; in humans, such disorders include Tay Sachs disease and Gaucher disease.
"In theory, the approach should be applicable to other lysosomal storage diseases, with the exception of those that affect the central nervous system," said Ponder, associate professor of medicine and assistant professor of biochemistry and biophysics at Washington University. "We're hopeful that the approach might also be applicable to hemophilia."
Lysosomal storage diseases such as MPS VII can be treated through enzyme replacement therapy, but that approach requires regular intravenous injections and is prohibitively expensive. Bone-marrow transplantation is another option but is risky, and compatible donors are often unavailable.
MPS diseases affect 1 in 27,000 live births among humans, but the disease is debilitating for patients and emotionally wrenching for their families. Human symptoms include growth retardation, mobility problems, facial deformities, corneal clouding, heart-valve and liver abnormalities and mental retardation, among others. Most patients die in childhood.
"The gene therapy research of Drs. Haskins, Ponder and collaborators involving MPS VII dogs has significant implications for all MPS disorders," said Barbara Wedehase, executive director of the National MPS Society, an organization of parents of children with MPS. "Their current and ongoing research will provide new insights into the treatment of individuals affected with these devastating disorders."
In these experiments, two- to three-day-old dogs with MPS VII received four simple intravenous injections of a retroviral vector expressing canine beta-glucuronidase. The vector used was made from the Moloney murine leukemia virus with a liver-specific promoter; at several days of age, canine liver growth is so rapid that transduction occurs readily and beta-glucuronidase is secreted continuously into the bloodstream.
The enzyme's activity was subsequently found at normal, stable levels for up to 14 months in the treated dogs; one dog has produced 60 times normal enzyme for 17 months. Unlike other dogs with MPS VII, the treated dogs gained weight normally, attaining nearly 90 percent the weight of their unaffected littermates, and avoided the serious side effects normally associated with lysosomal storage diseases. The beta-glucuronidase gene does not appear to have been inserted into the germ line.
Haskins and Ponder were joined in the research by John R. Melniczek, Margaret A. Weil, Thomas M. O'Malley, Patricia A. O'Donnell, Van W. Knox, Hamutal Mazrier, N. Matthew Ellinwood, Meg Sleeper, Susan W. Volk, Jean Zweigle and John H. Wolfe of Penn's School of Veterinary Medicine; Albert M. Maguire of Penn's School of Medicine; Lingfei Xu and Robert L. Mango of Washington University's School of Medicine; and Gustavo D. Aguirre of Cornell University's College of Veterinary Medicine. The work was funded by the National Institutes of Health.
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