Gene Therapy Reverses Brain Function Impairment in Animal Model

Contact: Jennifer BrownHealth Science RelationsUniversity of Iowa(319) 335-9917[email protected]

Using an animal model of a human disease that causes mental retardation in young children, University of Iowa researchers and their colleagues at the University of Rochester have shown that brain-directed gene therapy not only prevents progression of the neurological disease, but also restores mental abilities in the animals. The study appears online in the April 16 Proceedings of the National Academy of Sciences (PNAS).

"This is the first time that recovery of neurological function has been shown to result from treatment initiated after the onset of the disease in an animal model," said Beverly Davidson, Ph.D., the Roy J. Carver Professor in Internal Medicine, and UI professor of physiology and biophysics, and neurology. "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."

The researchers conducted their experiments in a mouse model of Sly disease, a rare human disorder caused by the absence of an enzyme called beta-glucuronidase. Sly disease is a lysosomal storage disease, a group of disorders each caused by the deficiency of one enzyme from a family of enzymes that break down large molecules. The build-up of undegraded large molecules in tissues causes various problems, including mental retardation, vision loss, bone and joint disorders and organ failure.

Lysosomal storage diseases occur in around one of every 7,000 births and often affect brain tissue, causing progressive neurodegeneration. Childhood onset lysosomal storage diseases that affect the brain are fatal.

"These diseases are progressive, so patients are often normal at birth and then develop symptoms later on," Davidson explained. "We knew from prior work in animal models that we could protect against the onset of the disease with gene therapy. What had never been tested was whether we could correct the problem after disease onset. That is the key finding of this study."

Diseases caused by an insufficiency or loss of a particular protein can often be corrected by giving patients the missing protein. Using insulin (a small protein) to treat diabetes is an example of one type of protein replacement therapy.

Enzyme replacement therapies for several lysosomal storage diseases are currently in use or being tested and are proving useful in correcting symptoms in patients. However, when the brain is affected by this type of disease, the natural blood-brain barrier prevents corrective enzymes from getting into the brain from the bloodstream. Gene therapy, using a disabled virus to transport a gene into cells is one way to overcome the blood-brain barrier and deliver corrective genes directly to brain cells.

Feline immunodeficiency virus (FIV) is a useful vector for gene therapy to the brain because it allows for long-term and robust expression of the protein in brain tissue, and the immune system does not seem to overreact to virus presence. FIV also has never been shown to cause disease in humans.

Using disabled FIV, the researchers delivered beta-glucuronidase gene to brain cells of mice models of Sly disease. The mice treated with the gene therapy already had started to show the memory and spatial learning impairment that are characteristic of this neurodegenerative disease.

To determine the effect of the gene therapy, the researchers examined tissues and small molecular changes in the brains of treated mice. They also looked at the animals' behavior. As expected, the build-up of undegraded material in brain cells was corrected by the therapy, but the researchers also found that treated mice recovered mental abilities that had been disrupted by the disease.

Davidson said this is a very important finding because children with lysosomal storage diseases usually are diagnosed after the onset of the disease when symptoms such as mental retardation already have appeared. Thus, the goal of successful therapies is to rescue normal cognitive function and prevent disease progression.

In a commentary accompanying the study in PNAS, William S. Sly, M.D., at Saint Louis University School of Medicine, suggests that the work might be considered a "landmark study" because it demonstrated that brain-directed enzyme replacement initiated after the onset of the disease actually reversed established behavioral deficits.

"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," said Davidson, who also is associate director of the UI Center for Gene Therapy of Cystic Fibrosis and other Genetic Diseases.

How the enzyme replacement produces brain function recovery is a very complicated question and will be the focus of subsequent studies in Davidson's lab.

These findings also may have implications beyond developing treatments for lysosomal storage diseases, Davidson said. Understanding the molecular basis of neurological recovery, including which genes are involved, may help in understanding and treating certain other neurodegenerative diseases. This work could also lead to new pharmacological therapies for neurodegenerative diseases that alleviate symptoms and improve patients' well being.

In addition to Davidson, Colleen Stein, Ph.D., and Stephanie Hughes, Ph.D., UI postdoctoral researchers in internal medicine; Jason Heth, M.D., UI neurosurgery resident; and Andrew Brooks, Ph.D., research assistant professor of environmental medicine at the University of Rochester Medical Center made key contributions to the study.

The research team also included Paul McCray, M.D., UI professor of pediatrics; Deborah Cory-Slechta, Ph.D., and Howard Federoff, M.D., Ph.D., at the University of Rochester Medical Center; and Sybille Sauter, Ph.D., and Julie Johnston, Ph.D., at Chiron Technologies, San Diego.

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