Trends in Neurosciences
Volume 20, Issue 7, 1 July 1997, Pages 277-279
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The coming of age of the GDNF family and its receptors: gene delivery in a rat Parkinson model may have clinical implications

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Clinical hopes and concerns

As for all newly discovered trophic factors, there is hope that GDNF might become useful in the treatment of nervous system disease. Given its spectrum of demonstrated activities which includes, but is not limited to, potent trophic actions on dopamine neurons, motoneurons and peripheral ganglia2, 9, 10, 11, 12, these hopes include treatments for Parkinson's disease, ALS, and peripheral neuropathies. Perhaps the best-studied experimental model to date in which GDNF has proven effective is that

How to increase the level of a trophic factor in the brain

In addition to the direct stereotaxic protein injection approach, there are many additional ways in which the goal of controlling the level of a trophic factor in the CNS might be achieved (see Ref. [16]). One set of techniques utilizes the protein itself: implantable, biodegradable, slow-release preparations containing the protein can be used to obtain long-term localized release. Another approach is to cross the blood-brain barrier, for instance by coupling the active protein to a molecule

Intracerebral GDNF gene delivery rescues neurons

Recently, Choi-Lundberg and colleagues[18]reported that a replication-deficient adenoviral vector carrying the human GDNF gene, when injected into the mesencephalon of rats, could protect dopamine neurons from undergoing 6-OHDA-induced degeneration. In these experiments the authors first labeled dopamine neurons by retrograde filling with fluorogold injected into the terminal areas in striatum. One week later, the DA neurotoxin 6-OHDA was injected into one striatum[19]and the ensuing loss of DA

How long will transgenes stay active?

Choi-Lundberg and colleagues measured levels of DNA, RNA and protein in mesencephalon following injections of the viral constructs and found significant amounts after one week. While GDNF protein was still detectable after four weeks by ELISA, levels of both protein and RNA (but not DNA) had dropped to about a third of the levels noted at one week. The authors therefore suggest that there had been a down-regulation of the Rous sarcoma virus promoter used to drive the expression, rather than a

Can transgene expression be directed and controlled?

In the reported experiments[18], infected cells probably included some of the DA neurons themselves, since control animals infected with lacZ and a nuclear-localizing signal had DA neurons that could be double-labeled for β-galactosidase (the product of the lacZ gene) in the nucleus, and tyrosine hydroxylase (a marker of DA neurons) in the cytoplasm. It is not known if DA neurons can utilize self-produced GDNF, but following release autocrine or paracrine effects appear likely, given the

The long and winding road to possible clinical applications

Trophic factors are characteristically very potent and always have a rather wide spectrum of effects. Therefore delivery of trophic factors in a highly localized fashion may be necessary to avoid unwanted effects. For instance, when NGF was delivered directly into putamen of patients with Parkinson's disease (to support grafts of adrenal medullary tissue) there were no noticeable side effects[15]. However, when NGF was delivered to the CSF of patients with Alzheimer's disease (to stimulate

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