Public Release: 

New gene therapy promising for treating Fabry disease

Treatment successful in mice

University of Toronto

Researchers at the University of Toronto have developed a gene therapy that shows promise for early and sustained correction of Fabry disease, an inherited disorder whose sufferers have a life expectancy of only 40 to 50 years.

Fabry disease is one of about 40 lysosomal storage disorders that collectively affect approximately one in 7,700 people. Due to genetic defects, Fabry patients have a buildup of lipids (fats) in endothelial cells lining vessel walls, causing constriction. Eventually, cardiac disease, kidney disease or strokes result.

"Patients with Fabry disease either don't make enough of the enzyme alpha-galactosidase A or improper synthesis means the enzyme isn't active enough," says Jeffrey Medin, a U of T associate professor in the Department of Medical Biophysics and a scientist with the Ontario Cancer Institute at the Princess Margaret Hospital, one of three teaching hospitals of the University Health Network.

In research published in the Nov. 15 edition of the Proceedings of the National Academy of Sciences of the U.S.A., Medin and his colleagues demonstrated that an engineered lentiviral vector - a type of retrovirus - 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. Further testing will be required before the therapy can be tried in humans.

"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 consequences became irreparable."

A therapeutic vector was employed to deliver the corrective gene. Throughout a significant portion of their lives, the corrected Fabry mice showed a sustained level of enzyme production at approximately 50 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.

In a parallel study, Medin and his colleagues were able to monitor gene therapy vector activity in treated live mice at various points in their lives over a significant time-span using a marker gene and bioluminescent imaging. They tracked the marking enzyme's activity in the body and in various individual organs, including the brain.

Medin's findings have special relevance in Canada. There is a significant concentration of Fabry patients in Nova Scotia, all descended from an immigrant who arrived there in the late 1600s.

Presently, the only corrective treatment option for people with Fabry disease is a very costly course of treatment requiring weekly or bi-weekly recombinant enzyme infusions done in a hospital. Corrective gene therapy, if approved for human use, would possibly translate to a one-time treatment.

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This research was supported in part by the U.S. National Institutes of Health and a fellowship from the National Organization for Rare Disorders. Other researchers involved in the project include U of T post-doctoral fellows Makoto Yoshimitsu, Takeya Sato and Jagdeep Walia, technicians Kesheng Tao, Gillian Sleep, Armando Poeppl and John Underwood, lab manager Vanessa Rasaiah, Dr. Lori West from the Hospital for Sick Children and Dr. Roscoe Brady, National Institutes of Health.

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