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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