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Old Drug May Offer New Hope to
Victims of Childhood Neuro-Degenerative Disease
A drug long used to treat a rare genetic disease also has
the
potential to treat a form of Batten disease, a fatal group of
hereditary
disorders that gradually robs its victims of their eyesight
and mental
abilities before claiming their lives.
The laboratory study, appearing in the April 1, 2001 Nature
Medicine, was
conducted by researchers at the National Institute of Child
Health and Human
Development (NICHD) and the Institute for Basic Research in
Developmental
Disabilities in Staten Island, New York. The researchers are
now seeking
patients with this form of Batten disease to test whether the
drug
phosphocysteamine will be an effective treatment for them.
"This is an extremely promising lead," said Duane
Alexander, M.D.
Director of the NICHD. "The NICHD team has shown in laboratory
studies that
phosphocysteamine breaks down the toxic compound responsible
for a Batten
disease variation which leaves its victims without higher brain
function by
the time they reach their fourth birthday."
Batten disease is a relatively common (one in 12,500 births
worldwide) group of genetic disorders of the nervous system
that begin in
early childhood. These disorders result from the buildup of
substances
called lipopigments in the body. The NICHD researchers found
that
phosphocysteamine breaks the lipopigments apart, into the lipids
(fats) and
proteins that comprise them. The NICHD researchers concentrated
their
efforts on the form of Batten Disease known as infantile neuronal
ceroid
lipofuscinosis (INCL), which claims the lives of its victims
much earlier
than do the other forms of the disease. Estimates of INCL's
frequency in
the United States do not exist, but researchers believe it is
uncommon.
Phosphocysteamine has been approved for use in patients by the
U.S. Food and
Drug Administration. Another team of NICHD scientists pioneered
the drug as
a treatment for cystinosis, a rare hereditary disorder that,
if untreated,
results in blindness, kidney failure, and death by about age
nine. The
authors of the current study noted that cystinosis patients
have used
phosphocysteamine safely for more than 20 years.
Also called Santavuori-Haltia disease, INCL strikes between
six
months and two years of age. Children who have the disorder
lose their
eyesight by age two, experience frequent seizures, and deteriorate
mentally
until their brain has no cortical activity at three to four
years of age.
They live in this vegetative state until about eight to twelve
years of age,
when they die.
INCL is caused by a defect in the gene that provides the information
for palmitoyl-protein thioesterase (PPT), according to the study's
senior
author, Anil B. Mukherjee, head of the NICHD's Section on Developmental
Genetics. As a result of normal chemical reactions in the cell,
any number
of different kinds of proteins bind chemically with lipid molecules.
These
protein and lipid molecules are then transported inside lysosomes-minute,
balloon-like sacs within the cell.
Ordinarily, PPT breaks the bonds that hold the proteins and
lipids together,
which allows the newly separated molecules to be broken down
and transported
to other parts of the cell. Because children with INCL lack
PPT, the
protein-lipid complexes accumulate within their lysosomes. Eventually,
the
lysosomes grow so large they eventually kill the cell.
Dr. Mukherjee and his coworkers tested laboratory cultures
of cells taken
from patients with INCL. The researchers found that phosphocysteamine
reduced the amount of protein-lipid complexes within the lysosomes
to
minimal levels. Additional doses of the drug prevented the complexes
from
reaching toxic levels.
Dr. Zhongjian Zhang, the first author of the study, said "We're
extremely
excited by the possibility that this drug might improve the
lives of
patients." This study was supported by a "bench-to-bedside"
award from the
Clinical Center of the National Institutes of Health (NIH) and
a clinical
trial is now scheduled to start shortly for patients with the
most severe
form of INCL.
The NICHD is part of the NIH, the biomedical research arm
of the federal
government. The Institute sponsors research on development before
and after
birth; maternal, child, and family health; reproductive biology
and
population issues; and medical rehabilitation. NICHD publications,
as well
as information about the Institute, are available from the NICHD
website,
http://www.nichd.nih.gov,
or from the NICHD Clearinghouse, 1-800-370-2943;
E-mail NICHDClearinghouse@mail.nih.gov.
A fact sheet on Batten Disease is available from the National
Institute of Neurological Disorders and Stroke, at
http://www.ninds.nih.gov/health_and_medical/disorders/batten.htm.
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Stephanie Clipper
Public Liaison Officer
NINDS-OCPL
31 Center Drive
Room 8A16, MSC 2540
Bethesda, Maryland 20892-2540
ph: (301) 496-5751
fx: (301) 402-2186
sc59t@nih.gov
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