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Science News

PDF Interprets: Scientists Identify a New Way of Delivering GDNF, A Treatment in the Pipeline for Parkinsonís

Researchers say they may have found a way to deliver glial-derived neurotrophic factor, or GDNF, according to a report published in the August advance online version of Molecular Therapy.

Several years ago, GDNF initially showed promise for treating Parkinson’s disease (PD), but clinical trials were halted reportedly because of mixed results and because of concerns about safety.  Ronald Mandel, Ph.D., and colleagues at the University of Florida, Gainesville, report their development of a new delivery method of the potential therapy – specifically, a controllable viral vector that allows for a reversible expression of GDNF. 

GDNF is a neurotrophic factor that nourishes new brain cells and guides their connections during prenatal development.  Scientists who study Parkinson’s have put major emphasis on finding ways to prolong the survival of the dopaminergic neurons affected by PD in the substantia nigra of the brain.  So, they  have looked at GDNF because of the role it plays in the development of the dopaminergic neurons affected by Parkinson’s.  Although its role is reduced in adults, it remains critical for dopaminergic cell survival. 

Previous clinical trials of GDNF delivered the factor directly to affected sites in the brain using implanted catheters.  Early trials produced some limited positive results, but the effects were inconsistent.  Additionally, the method presents risks such as surgical complications and side effects.  Another method of delivery of GDNF, the use of viral vectors, has been tested in animals, and has been successfully used with promising results for protection of dopaminergic neurons against parkinsonian pathology.  However, this method has its own risks.  Expression levels resulting from viral vectors have varied widely in among different studies and scientists had no way to control or stop the expression.  Yet long-term overexpression of GDNF has the potential for serious side effects. 

Therefore, a control mechanism for gene therapy could improve both the safety of continued human trials and the knowledge scientists can take away from such studies.

Dr. Mandel and his team report their development of a controllable viral vector for transgene delivery.  They say that it would improve upon previously tested viral vectors because it would allow a reversible expression of GDNF.  Researchers could control the gene's expression once it was inside the brain. 

Researchers say that in their study, the recombinant adeno-associated viral (rAAV) vector that they  used responded to the antibiotic doxycycline, which caused a complete and reversible suppression of GDNF expression when introduced to the test animals’ food.  In addition, the researchers took advantage of a previous finding that GDNF overexpression in the substantia nigra leads to weight loss in aged rats.  They were thus able to use weight measurements as a measurement for gauging induced GDNF expression levels throughout repeated episodes of doxycycline on/off switching of the transgene.  The dose-response data obtained by the authors suggested that the level of GDNF expression required to produce a therapeutic response was far below levels expected to cause either weight loss or toxic effects, with doxycyline suppression of the transgene available as a safety measure in future trials.

The report could be an important step toward safe clinical trials of gene therapy for Parkinson’s disease in humans.

Source Date: Sep 22 2009