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Release:April 16, 2002
UI team reverses brain function impairment in animals
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
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
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
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.
University of Iowa Health Care describes the partnership between
the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and
Clinics and the patient care, medical education and research programs and
services they provide. Visit UI Health Care online at www.uihealthcare.com.