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Regulated rAAV-GDNF to treat Parkinson's disease: Translational research plan

This grant builds upon the research from a prior grant: rAAV-ribozyme Mediated Parkin Knockdown as a Pre-clinical Model of Parkinson's Disease

We are attempting to perfect gene therapy using glial cell line-derived neurotrophic factor (GDNF) for Parkinson’s disease. One part of developing this gene therapy is engineering the ability to turn off GDNF delivery using the common antibiotic, doxycycline. There are some significant fundamental unknowns regarding doxycycline delivery in pre-clinical models which we hope will model the situation in humans. This project is designed to test 1) Does doxycyline cross into the primate brain? And 2) if so, can we turn off gene delivered GDNF?

Project Description
We will administer doxycyline to pre-clinical models at different doses and determine blood levels of doxycycline with the goal of obtaining about 20% of the antibiotic blood level. Then, when we know how much doxycycline to administer, we will determine whether there is measurable doxycyline in the cerebrospinal fluid. If we can measure doxycycline in the cerebrospinal fluid we will then delivery recombinant adeno-associated virus carrying the GDNF gene under the control of a doxycycline responsive turn-off system. This will give us an initial idea of whether this strategy might be feasible in humans.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
This may be a major step forward in developing a regulated GDNF treatment for early stage PD.

Anticipated Outcome
We have data that the regulated GDNF system works perfectly in prior pre-clinical models. Therefore, we expect that if doxycycline does cross into the brain, then we will be able to turn off GDNF expression in the brain. These results will enable us to apply for grants to fund FDA level pre-clinical studies accrue the data necessary to apply to use this gene therapy strategy in humans.

Final Outcome

GDNF, a trophic factor, has been shown to be protective in several pre-clinical models of Parkinson’s disease (PD). Unfortunately, clinical trials where GDNF was injected directly into the brain or gene therapy trials where a sister protein was used to deliver the trophic factor have failed.  However, we believe that gene transfer is the correct way to deliver GDNF to humans for treatment of PD and the reason the trials have failed is that the patients were too late stage.  In theory, GDNF should slow the progression of the disease, therefore end stage patients don’t benefit from GDNF.  In order to make GDNF gene therapy safer, we have developed a method to externally control GDNF so that if there are unacceptable side-effects, GDNF can be turned off. We believe this safety improvement may allow clinical trials in early stage PD patients and increase the chances that GDNF will have demonstrably positive effects.

This project was designed to show 1) that the external GDNF controlling drug, doxycycline (a FDA approved antibiotic) crosses the blood brain barrier in pre-clinical models and 2) to show that we can turn GDNF off in the brains of pre-clinical models using low-dose doxycycline. First, we showed that doxycycline crossed the blood brain barrier in our model at a rate seen in other pre-clinical models. We injected the regulated GDNF vector, with and without doxycycline.  We found GDNF in the brains of the pre-clinical model without doxycycline and no GDNF in the brains of those that received doxycycline. We believe we have demonstrated that our gene regulation system works well in a pre-clinical model.


  • Ronald J. Mandel, PhD

    Gainesville, FL United States

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