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Gene Therapy Repairs Neurological Damage in Animal Model for Rare Metabolic Disease

For release: Tuesday, May 14, 2002

Using a disabled virus, researchers have delivered corrective genes directly to the brain cells of mice affected by a rare lysosomal storage disease that causes mental impairment. The treatment not only halted progression of the disease but also restored spatial learning and memory in the mice. The study is the first to suggest that cognitive problems associated with a neurodegenerative disease might be reversed after the disease has begun.

"This is the first time that recovery of neurological function has been shown to result from treatment initiated after the onset of a neurodegenerative disease in an animal model," says Beverly Davidson, Ph.D. at the University of Iowa, who led the study. "Knowing that, at least in our animal models, recovery is possible, gives us hope that therapies initiated after disease onset in humans will have a positive effect on the neurological dysfunction caused by this type of disease in humans." Current treatments for neurodegenerative diseases can only stop or slow neurological damage, not reverse it. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the April 16, 2002, early edition of the Proceedings of the National Academy of Sciences (PNAS) .1

Lysosomal storage diseases (LSDs) are a group of hereditary disorders caused by defective genes that keep the body from producing particular enzymes that break down complex molecules in the body. Each enzyme breaks down a specific portion of the molecule. The build-up of these molecules inside cells causes various problems, which may include mental retardation, vision loss, bone and joint disorders, and organ failure. An LSD occurs in approximately 1 out of every 7,000 births. Most of these diseases affect the brain and are fatal. The disease in this study, called Sly disease or mucopolysaccharidosis type VII (MPS VII), is a rare LSD caused by the absence of an enzyme called beta-glucuronidase.

Enzyme replacement therapies for several lysosomal diseases, such as Gaucher's and Fabry's diseases, are currently in use or being tested and have proven useful in correcting non-neurological symptoms and pain. But the blood-brain barrier (a type of cellular "wall" that blocks foreign substances) prevents corrective enzymes from entering the brain via the bloodstream. Brain-directed gene therapy, using a disabled virus to transport the gene into the brain following direct delivery, is one way to get past the blood-brain barrier.

"These diseases are progressive, so patients are often normal at birth and then develop symptoms later on," says Dr. Davidson. Previous studies in a mouse model for Sly disease had shown that therapy initiated soon after birth could prevent the onset of spatial learning and memory impairments, such as the inability to remember where objects are in a maze. However, researchers had never tested whether they could correct these problems after onset of the disease.

Dr. Davidson and her colleagues used a disabled feline virus to deliver the missing gene for beta-glucuronidase to the brains of 18-week-old mice with the defective gene for Sly disease and significant learning impairments. To determine the effect of the gene therapy, Davidson and her team examined brain tissue, looking for changes at the molecular level. They also conducted tests designed to reveal changes in memory and spatial learning skills.

As expected, the viral-delivered gene therapy stopped the build-up of storage material in brain cells and increased the beta-glucuronidase output. But the researchers were surprised to find that the mice's performance in learning and memory tests had significantly improved. The treated animals also had increased activity of several genes that have been linked to learning and memory.

The researchers do not know how gene therapy for this disease prompts recovery of learning and memory in the mice. They are now planning studies to try to answer that question.

"Although our animal model mimics a very rare lysosomal storage disease, we think that our findings are likely to be applicable to many of these disorders," Dr. Davidson says. The findings also may help researchers understand how animals recover memory and other neurological functions, which could point to new ways of treating many neurodegenerative diseases.


1 Brooks AI, Stein, CS, Hughes SM, Heth J, McCray PM, Sauter SL, Johnston JC, Cory-Slechta DA, Federoff HJ, Davidson BL. "Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors." Proceedings of the National Academy of Sciences Early Edition, April 16, 2002, .

2 Sly, WS and Vogle C. "Commentary: Brain-directed gene therapy for lysosomal storage disease: Going well beyond the blood brain barrier." Proceedings of the National Academy of Sciences , Vol 99, Issue 9, April 30, 2002, pp. 5760-5762.


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Last Modified February 23, 2016