GDNF Gene Therapy Protects Dopaminergic Neurons
http://www.reutershealth.com/news/docs/199702/19970207sca.html
WESTPORT, Feb 07 (Reuters) - In rats, glial-derived neurotrophic
factor (GDNF) gene therapy ameliorates the effect of
experimentally induced degeneration of dopaminergic neurons,
pointing to a hopeful new approach to treating Parkinson's
disease.
Dr. Martha Bohn of the University of Rochester, Rochester, New
York, describes the findings in the journal Science today:
"[GDNF] supports growth and survival of dopaminergic (DA)
neurons. A replication-defective adenoviral (Ad) vector encoding
human GDNF injected near the rat substantia nigra was found to
protect DA neurons from the progressive degeneration induced by
[a] neurotoxin...injected into the striatum." GDNF-treated rats
had roughly a three-fold reduction in neuronal loss compared with
untreated rats.
"It is not known how closely neurotoxin-induced lesions mimic the
state of diseased neurons in humans with Parkinson's' disease,"
Dr. Bohn notes. "The mechanism of [dopaminergic] neuronal loss in
Parkinson's disease is unknown...[however] GDNF gene therapy is
likely to protect diseased human neurons, regardless of the
mechanism of degeneration involved."
Dr. Gene Redmond of Yale comments in University press release:
"There has been a great deal of work suggesting that GDNF might
be useful in the brain; the critical limiting factor has been the
lack of an appropriate long-lasting method of delivery. Packaging
GDNF in a viral vector and inserting it directly into brain cells
is quite ingenious."
Science 1997;275:838-841.
-Westport Newsroom 203 221 7648
------------------------------
Promising Gene Therapy For Parkinson's
http://www.reutershealth.com/news/rhdn/199702/1997020608.html
NEW YORK, Feb 06 (Reuters) -- An experimental gene therapy
treatment could help protect key brain cells from degenerating
and dying in patients with Parkinson's disease, a new study in
animals suggests.
Researchers inserted a gene for a nerve-cell protecting protein
into a common-cold virus, and injected the modified virus into
the brains of rats. The rodents -- who had Parkinson's-like
symptoms induced by a chemical -- were three times less likely to
have nerve cells die over the following six-week period if they
were given the new treatment, according to the report in this
week's issue of Science.
"While this work is a long way from clinical applications in
humans, it is a prime example of potential in vivo gene therapy
in the brain," stated lead study author Derek Choi-Lundberg in a
release from the University of Rochester in New York. The study
was conducted by scientists at the University of Rochester, a
Gaithersburg, Maryland-based company, Genetic Therapy, Inc., and
the University of Iowa College of Medicine in Iowa City.
For several years, researchers have known that a protein called
glial cell line-derived neurotrophic factor, or GDNF, promoted
the survival of the dopaminergic neurons, which are nerve cells
found in pea-sized section of the brain, the substantia nigra. In
Parkinson's disease, the gradual degeneration and death of such
nerve cells cuts off the brain's supply of the neurotransmitter
dopamine, causing the tremors, shuffling gate, muscle rigidity
and weakness that are characteristic of the disease. While GDNF
has been recognized to help protect dopaminergic neurons in
animal studies, experimental treatments required repeated
injections of the protein into the brain.
In the new research, the gene for making GDNF was inserted into
an adenovirus that had been modified to allow it to infect cells
-- but not to reproduce itself. Once the virus had delivered the
gene into brain cells, the cells began producing GDNF on their
own.
Overall, only 21% of the nerve cells degenerated in the treated
rats, compared with 69% of those in the untreated rodents.
However, the amount of GDNF tended to decrease over time,
possibly because of an immune response to the virus, according to
the report.
Stable gene expression may be achieved in the future through the
use of new types of modified viruses, or non-viral methods of
gene transfer, "that will eliminate or minimize the expression of
viral genes and host responses to the vectors," the authors
wrote. Much more study is needed to determine if the therapy
could be safe and effective in humans with Parkinson's disease.
Patients with the disease are most often treated with levodopa, a
precursor of dopamine that may be effective for only a short time
and that has side effects, such as nausea, vomiting and
confusion. About 500,000 people in the U.S. have Parkinson's
disease, which most often strikes after age 60.
SOURCE: Science (1997;275:838-841)
---------------------------------
Lewy Bodies Linked To Neuronal Death
http://www.reutershealth.com/news/docs/199702/19970204scc.html
WESTPORT, Feb 03 (Reuters) - Scientists at the University of
Pennsylvania and elsewhere have shown in animal studies that Lewy
bodies may play a heretofore overlooked role in the development
of Parkinson's disease or diffuse Lewy-body dementia.
"There are many people in the field who see Lewy bodies as useful
diagnostic markers, but without significant implications for the
health and welfare of neurons," Dr. John Q. Trojanowski explains
in a UPenn press release. "What our study suggests is that this
view is incorrect...Lewy bodies are not just innocuous trash that
accumulates in the cells over time, but, indeed, may compromise
the longevity of neurons."
Dr. Trojanowski's team developed transgenic mice expressing "...a
fusion protein composed of a truncated high-molecular-weight
mouse neurofilament (NF) protein (NFH) fused to [the enzyme]
beta-galactosidase (LacZ)." The animals developed
neurofilament-rich aggregates, or NF inclusions, in neurons that
resemble Lewy bodies in Parkinson's disease. The researchers
found that the inclusions in Purkinje cells contained numerous
entrapped organelles (type II), and these cells began to
deteriorate at about 1 year and were eliminated by 18 months. On
the other hand, inclusions in hippocampal cells did not contain
organelles (type I) and these cells were not lost with age.
"[O]ur data suggest that the selective degeneration of Purkinje
cells in the...transgenic mice could result form the entrapment
of vital cellular organelles in type II NF-rich
inclusions...leading to the functional isolation of these
organelles, thereby compromising the long-term viability of
Purkinje cells," Dr. Trojanowski concludes in the February 1
issue of the Journal of Neuroscience. "Indeed, similar to human
neurodegenerative diseases such as [Parkinson's disease] and
[diffuse Lewy body disease], the loss of Purkinje cells in the
[transgenic] mice was an age-dependent and protracted process."
The scientists say the finding may provide a framework for
developing therapies aimed at the prevention or elimination of
Lewy bodies.
J Neuroscience 1997;17:1064-1074.
-Westport Newsroom 203 221 7648
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